Title:
Magnetic Nanoparticle Targeting of a 3D Bioprinted Model of Pulmonary Vasculature to Address Restenosis
Magnetic Nanoparticle Targeting of a 3D Bioprinted Model of Pulmonary Vasculature to Address Restenosis
Author(s)
Zanella, Stefano
Advisor(s)
Serpooshan, Vahid
Bauser-Heaton, Holly
Dasi, Lakshmi
Davis, Michael E.
Bauser-Heaton, Holly
Dasi, Lakshmi
Davis, Michael E.
Editor(s)
Collections
Supplementary to
Permanent Link
Abstract
Pulmonary Vein Stenosis (PVS) is a cardiovascular condition characterized by progressive lumen size reduction in one or more of the pulmonary veins. Central characteristics associated with pathological PVS state include the overgrowth of connective tissue and the deposition of fibrotic tissue within the lumen of the affected vessels. Neointimal lesions in PVS are characterized by deposition of myofibroblast-like cells which originate, in part, from vascular endothelial cells (ECs), a process known as endothelial-to-mesenchymal transition (EndMT), during which ECs lose their lineage-specific cell markers and take on myofibroblast properties. These cells can then move into the neointima, proliferate, secrete extracellular matrix (ECM) proteins, and form stenoses.
As a result of these uncontrolled cellular overgrowths, typical in PVS, the condition causes obstruction of blood flow from the lungs to the heart and can result in elevated pulmonary venous pressure, pulmonary hypertension, potentially cardiac failure, and death.
Current treatment options for PVS are limited to the use of catheterization or
surgery techniques to keep the veins patent. Furthermore, these methods only remove the lesion cells and cannot prevent their regrowth and restenosis. Currently, there are no treatments that can ensure a long-lasting control over restenosis mechanisms in the surgically treated pulmonary veins. Untreated restenosis can ultimately lead to catastrophic outcomes for the patient, including impairment of cardiac functions, hypoxia, and even death. Recent clinical trials have demonstrated that adding chemotherapy (systemic administration of anti-proliferative drugs) to the standard treatment regimens can significantly inhibit the abnormal cellular growth, and hence, reduce the risk of restenosis. However, noticeable toxic side-effects have been reported from such systemic delivery of antiproliferative drugs.
In this thesis work, we investigated a novel approach involving the delivery of
magnetic nanoparticles (NPs), coated with an anti-proliferative drug (rapamycin), to locally control cellular overgrowth in a 3D bioprinted in vitro model of pulmonary vasculature. Bioprinted bifurcated vein-like constructs with 2 mm lumens were seeded with human ECs and perfused using a custom-designed bioreactor platform to simulate the in vivo flow hemodynamics. Computational flow dynamics (CFD) modeling identified a vascular geometry recapitulated by an idealized bifurcation intersection model as a region at high risk of (re)stenosis, with greatest levels of alterations in wall shear stress. A 3.96 mm rare-earth magnet was incorporated within the perfusion chamber to target NP delivery to this vascular region at risk of intimal hypoplasia. The results of this study demonstrated the robust capacity of the engineered model to recapitulate the flow perturbation and endothelial dysfunction in the context of PVS. Targeted delivery of rapamycin-loaded NPs was successfully conducted under a 7-day dynamic culture, yielding a significant impact on the human vascular cell proliferation and overgrowth within the lumen space. Together, these results support the robust potential of 3D bioprinted in vitro platforms, such as the one described here, to develop, analyze, and optimize novel pharmacotherapeutic approaches to treat PVS and be adapted to address other cardiovascular pathologies.
Sponsor
Date Issued
2022-12-02
Extent
Resource Type
Text
Resource Subtype
Thesis