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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.
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Patient-specific 3D in vitro modeling and fluid dynamic analysis of primary pulmonary vein stenosis
IntroductionPrimary pulmonary vein stenosis (PVS) is a rare congenital heart disease that proves to be a clinical challenge due to the rapidly progressive disease course and high rates of treatment complications. PVS intervention is frequently faced with in-stent restenosis and persistent disease progression despite initial venous recanalization with balloon angioplasty or stenting. Alterations in wall shear stress (WSS) have been previously associated with neointimal hyperplasia and venous stenosis underlying PVS progression. Thus, the development of patient-specific three-dimensional (3D)in vitromodels is needed to further investigate the biomechanical outcomes of endovascular and surgical interventions. MethodsIn this study, deidentified computed tomography images from three patients were segmented to generate perfusable phantom models of pulmonary veins before and after catheterization. These 3D reconstructions were 3D printed using a clear resin ink and used in a benchtop experimental setup. Computational fluid dynamic (CFD) analysis was performed on modelsin silicoutilizing Doppler echocardiography data to represent thein vivoflow conditions at the inlets. Particle image velocimetry was conducted using the benchtop perfusion setup to analyze WSS and velocity profiles and the results were compared with those predicted by the CFD model. ResultsOur findings indicated areas of undesirable alterations in WSS before and after catheterization, in comparison with the published baseline levels in the healthyin vivotissues that may lead to regional disease progression. DiscussionThe established patient-specific 3Din vitromodels and the developedin vitro–in silicoplatform demonstrate great promise to refine interventional approaches and mitigate complications in treating patients with primary PVS.
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- Award ID(s):
- 2044657
- PAR ID:
- 10569783
- Publisher / Repository:
- Frontiers
- Date Published:
- Journal Name:
- Frontiers in Cardiovascular Medicine
- Volume:
- 11
- ISSN:
- 2297-055X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fcvm.2024.1432784
