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

• Published in: Advanced science 2024-07, Vol.11 (26), p.e2400476-n/a
• Main Authors: Ning, Liqun, Zanella, Stefano, Tomov, Martin L., Amoli, Mehdi Salar, Jin, Linqi, Hwang, Boeun, Saadeh, Maher, Chen, Huang, Neelakantan, Sunder, Dasi, Lakshmi Prasad, Avazmohammadi, Reza, Mahmoudi, Morteza, Bauser‐Heaton, Holly D., Serpooshan, Vahid
• Format: Article
• Language: English
• Subjects: 3D bioprinting; Ablation; Bioprinting - methods; Cell Proliferation - drug effects; Congenital diseases; Constriction, Pathologic; Disease; Drug Delivery Systems - methods; Drug therapy; endothelial cell proliferation; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; In Vitro Techniques; magnetic nanoparticles; Magnetite Nanoparticles; Nanoparticles; Pathophysiology; Patients; perfusion bioreactor; Printing, Three-Dimensional; Pulmonary vasculature; pulmonary vein stenosis; Pulmonary Veins; restenosis; Sirolimus - administration & dosage; Sirolimus - pharmacology; Stents; targeted drug delivery; Veins & arteries
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202400476

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. Manufacturing a patient inspired A,B) 3D in vitro model of pulmonary veins using bioprinting C,D) together with drug‐loaded magnetic nanoparticles and perfusion bioreactor technologies E). The in vitro and in silico F) models serve as a robust platform to study endothelial cell response to microenvironment in the context of vascular stenosis, as well as targeted drug delivery and therapy G).