THESIS
2014
xxiii, 155 pages : illustrations ; 30 cm
Abstract
Cardiovascular disease such as coronary artery disease is the leading cause of death in
the modern society. Vascular stents or grafts are the most preferred prosthesis for treating
such disease. However, lack of multifunctionality of vascular stents or grafts in terms of
inhibiting blood coagulation and smooth muscle cell (SMC) growth while concurrently
promoting endothelialization has resulted in higher rates of complications that involve
thrombosis and restenosis. A wide variety of environmental cues, particularly surface
chemistry and substrate topography, have been shown to regulate blood and vascular cell
compatibility. Yet the impacts of these chemical and topographical regulators remain
insufficiently characterized, and little is known about the cooperative interplay betw...[
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Cardiovascular disease such as coronary artery disease is the leading cause of death in
the modern society. Vascular stents or grafts are the most preferred prosthesis for treating
such disease. However, lack of multifunctionality of vascular stents or grafts in terms of
inhibiting blood coagulation and smooth muscle cell (SMC) growth while concurrently
promoting endothelialization has resulted in higher rates of complications that involve
thrombosis and restenosis. A wide variety of environmental cues, particularly surface
chemistry and substrate topography, have been shown to regulate blood and vascular cell
compatibility. Yet the impacts of these chemical and topographical regulators remain
insufficiently characterized, and little is known about the cooperative interplay between
chemical and topographic cues in regulating blood and vascular cell compatibility. The
objective of this study is to systematically investigate the individual and combined effects of
these two types of cues on blood and vascular cell compatibility.
Polydopamine (PDA), a mussel adhesive protein inspired coating, was synthesized on
TiO
2 surfaces by simple dip-coating method. It was demonstrated that surface characteristics
and functionalities of the PDA coating could be readily tuned by varying the initial dopamine
concentrations. Moreover, it was provided some new insights into the PDA structure through
systematic characterizations. Furthermore, the blood and vascular compatibility of the PDA
coating was further explored. The results indicated that the PDA coating significantly
promoted endothelial cell (EC) attachment, proliferation, focal adhesion formation, and stress
fiber development. In contrast, the PDA coating potently inhibited SMC proliferation. It was
proposed that the co-existence of quinone and reactive phenolic hydroxyl groups may be
crucial for achieving vascular cell selectivity. These data suggest the promising application of the PDA coating in the vascular stents or grafts.
Next, a novel patterned platform featuring two typical geometries (groove and pillar) and
six pattern sizes (0.5–50 μm) in a single substrate was developed to evaluate the response of
vascular cells and platelets. The results indicated that targeted multifunctionality can be indeed
instructed by rationally designed surface topography. The pillars non-selectively inhibited the
growth of ECs and SMCs. By contrast, the grooves displayed selective effects: in a
size-dependent manner, the grooves enhanced endothelialization but inhibited the growth of
SMCs. Moreover, it was suggested that topographic cues can affect response of vascular cells
by regulating focal adhesion and stress fiber development, which define cytoskeleton
organization and cell shape. Notably, both the grooves and the pillars at 1-μm-size drastically
reduced platelet adhesion and activation. Importantly, these findings suggested that the
topographic pattern featuring 1-μm grooves might be the optimal design of surface
multifunctionality that favors vascular cell selectivity and improves hemocompatibility.
To further expand the study, a facile and effective PDA-mediated approach was
developed to immobilize heparin onto topographically patterned substrate, and the combined
effects of these cues on blood and vascular cell compatibility were systematically investigated.
It was observed that immobilized heparin and substrate topography cooperatively modulated
anti-coagulation activity, EC attachment, proliferation, focal adhesion formation, and
endothelial marker expression. The substrate topography was the primary determinant of cell
alignment and elongation, driving in vivo-like endothelial organization. Importantly, combining
immobilized heparin with substrate topography empowered substantially stronger competitive
ability of ECs over SMCs than each cue itself. Moreover, we clearly elucidated the cooperative
interplay between immobilized heparin and substrate topography by a proposed and further
testified model.
This fundamental and systematic study is expected to further the understanding of
vascular cell-substrate interactions, and contribute to the future design of new generation of
vascular stent or graft systems.
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