Development and Evaluation of 3D-Printed Cardiovascular Stents
Date
2022Metadata
[+] Show full item recordAbstract
Biodegradable stents (BDS) could be a promising alternative to the conventional metallic stents for the treatment of atherosclerosis which is a coronary artery disease (CAD). Three-dimensional (3D) printing technique has offered easy and fast fabrication of BDS with enhanced reproducibility and efficacy. Therefore, the main aim of the current study was to develop 3D-printed biodegradable cardiovascular stents. A combination of 2-hydroxy ethyl methacrylate (HEMA) and methacrylate graphene oxide (MeGO) was used to enhance the mechanical properties and loaded with resveratrol (RSL) to efficiently recover endothelial cell function. The biocompatibility of the 3D-printed stent was evaluated using in vitro cell culture studies and zebrafish embryo model.
The percentage changes in volume of stents fabricated using HEMA and HEMA-0.35MeGO were 36.7±4.7% and 7.7±1.6%, respectively after 24 hr. The remaining fractions of 3D stents after 21 days and their corresponding first-order degradation rates were 95.9±0.5% and 0.30±0.10 x 10-4/hr for HEMA, and 98.2±0.3% and 0.11±0.04 x 10-4/hr for HEMA-0.35MeGO. The addition of MeGO significantly (p<0.001) enhanced the stiffness of hydrogel inks for 3D stents, indicating Young’s moduli of 0.22±0.01x10-2 MPa and 0.41±0.01x10-2 MPa for HEMA and HEMA-0.35MeGO after 21 days. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay revealed that 3D stents loaded with RSL (~1 mM) exerted no cytotoxic effects on the human umbilical vein endothelial cells (HUVECs). The controlled release of RSL from the stent enhanced nitric oxide (NO) production, lowered the levels tumor necrosis factor (TNF)-α, and alleviated H2O2-induced oxidative stress in HUVECs.
The RSL-loaded 3D stents displayed maximum viability of HUVECs in presence of oxidized low-density lipoprotein (ox-LDL) and resulted in similar NO production like control group (52.8±0.4 μM and 51.9±0.8 μM), whereas lipopolysaccharides (LPS) treatment (10 μg/mL) significantly displayed higher amounts of NO (82.4±1.2 μM). The amounts of TNF-α and interleukin (IL)-β released from zebrafish embryos (1.8±0.8 and 1.9±0.2) in the group treated with the RSL-loaded 3D stents were significantly lower (p<0.001) than those from the LPS alone treated group (8.1±2.3 and 23.8±3.8, respectively). It was found that stents with RSL at a dose of 1 mM indicated no mortality during the developmental stages, but stents at a dose of 2 mM resulted a lowered survival rate (93.3±3.3%), shorter length of larvae, pericardial and yolk sac edemas of 53.3±23.3% and 3.3±3.3%, respectively.
The 3D-printed biodegradable stent based on HEMA-MeGO and loaded with RSL displayed excellent biocompatibility and mechanical properties. RSL released from 3D cardiovascular stents efficiently recovered the endothelial function. The 3D-printed stents with the loading dose of 1 mM RSL displayed good biocompatibility in the zebrafish embryo toxicity studies. The RSL-loaded 3D stents efficiently downregulated the pro-inflammatory cytokines, while producing minimal developmental defects in zebrafish embryos. The RSL-loaded 3D stents displayed good biocompatibility in both Raw 264.7 cells and zebrafish embryo models, guaranteeing acceptable host response in clinical application. Overall, our results demonstrated that RSL-loaded stents protect an organism against oxidative stress, while limiting developmental defects in zebrafish embryos.
Table of Contents
Introduction -- Parametric optimization of 3D printing process -- Evaluation of biodegradable 3D-printed cardiovascular stents -- Assessment of biocompatibility of 3D-printed cardiovascular stents -- Summary and recommendations
Degree
Ph.D. (Doctor of Philosophy)