| dc.description.abstract | Cardiovascular disease (CVD) accounts for one in every five deaths in the
United States alone due to occlusion in small diameter (< 6 mm) vessels. The current
treatment options includes bypass grafting; however, more than 30 percent of
patients do not have viable saphenous veins for autologous grafting [1]. Therefore,
tissue engineering is being considered as an alternative approach. The overall goals
of this project were to develop a tissue engineered vascular graft with the
incorporation of carbon monoxide releasing molecules (CORMs) and to determine
the impacts of carbon monoxide (CO) on endothelial cells (ECs) with the goal of
promoting a functional endothelium within the graft. This was accomplished through
two complementary studies: investigating the impacts of CO-loaded electrospun
scaffolds on ECs for cardiovascular applications and diffusion-based modeling of
drug delivery of gasotransmitters from tissue engineered scaffolds. In the first study,
we extended the maximum in vitro incubation time to permit better cellular
attachment and proliferation with a newly-synthesized, more hydrophobic CORM
(DK3) and established the impact of CORMs on EC viability and function (e.g.
reactive oxygen species (ROS) products, and ROS levels). We further investigated toxicity and biocompatibility of a newly synthesized CORM (DK4) loaded within
PCL thin films and nanoparticles. We concluded that the DK4 and other compounds
are not toxic at doses ranging from 0 – 50 μg/mL to the ECs both within nanoparticles
that can be internalized within cells. We also conducted an in vivo pilot study to
determine graft biocompatibility and preliminary results showed that CORM
implants maintain mechanical integrity, support blood flow, and do not show toxicity
for up to six weeks. In the second study, we validated a computational model and
analyzed the output of CO delivery to better understand and control local dose. For
CO release, this model is necessary because of the limitations with real-time
experimental analysis and the need to better understand the dose available to the
cells. We demonstrated that the validated model can be used to predict drug
availability to cells for a variety of scaffolds and drug molecules. Our simulated
results suggest that only a fraction of the initial concentration of gasotransmitters
released from fibers that enters the interstitial fluid in vivo, or culture media in vitro,
will be available to cells. We also demonstrated that fiber orientation and fiber
diameter are important for drug delivery, but fiber density provides even more
important information. The more contact area within the fiber scaffolds is equivalent
to experimental conditions with more cell attachment and spreading. These
parameters are not only important for traditional tissue engineering, but also for drug
delivery. Overall, these results demonstrate the feasibility of making a tissue
engineered vascular graft with the incorporation of CORMs and validating he
importance of computational modeling of diffusion-based transport of CO. Future work will involve performing surface modifications to enhance cell attachment and
proliferation, using the developed computational model to better predict dose
available to cells, and experimentally determining impact of CO dose on ECs. | en_US |
