Targeted Rapamycin Delivery via Magnetic Nanoparticles to Address Stenosis in a 3D Bioprinted in Vitro Model of Pulmonary Veins

Abstract

Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off‐target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin‐loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases.

Patient-specific 3D in vitro modeling and fluid dynamic analysis of primary pulmonary vein stenosis

“…3D PIV methods could be employed to better recapitulate the hemodynamic behavior in vitro or ex vivo . Furthermore, as previously demonstrated in PVS, PAA, and tetralogy of Fallot with MAPCAs, 3D bioprinted models could be developed, using hydrogel-based biomaterials and a variety of cell types, and used to study cellular and genetic responses to venous stenosis ( 29 , 41 , 45 – 47 ). Using 3D bioprinted models, spatial transcriptomics and/or proteomic analyses could be highly informative tools to study genetic implications associated with the altered cellular microenvironment observed in primary PVS.…”

“…Similarly and in parallel to the in silico models, in vitro PIV methods have been proven to be a valuable experimental technique to study flow characteristics in cardiovascular models ( 29 , 39 , 40 ). Through the use of laser or ultrasound-based approaches, PIV techniques have enabled precise tracking of flow within the 3D geometries and quantifying fluid flow parameters such as planar and 3D WSS and velocity vectors, which are critical factors in the pathogenesis of congenital pulmonary vascular disease ( 29 , 34 , 41 ).…”