Nano-scale design of cardiovascular biomaterials
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Fatemeh Karimi
Cardiovascular disease is the leading cause of death worldwide. The development of blood-compatible biomaterials could relieve this burden by improving the performance of cardiovascular devices such assmall-diameter vascular grafts. An attractive strategy for improving blood compatibility of an interface is to generate biomaterials that foster a confluent and functioning endothelial cell layer. Although several strategies have been explored to improve endothelialisation, there are still no commercially available blood-compatible grafts that promotes endothelialization. The lack of a blood-compatible interface is one of the most pressing challenges in the biomaterials field. As such, additional research is required in order to develop new technologies to meet this need. The aim of this work is to design a biomaterial that promotes endothelialization by mimicking cellextracellular matrix interactions. In order to achieve this, we used two biomimetic approaches: (1)nanoclustering of cell adhesive ligands (ligand multivalency) to promote the clustering of cell receptors, especially integrin receptors, and (2) dual functionalization of materials with both integrin- and syndecan-binding ligands to engage both cell receptor types to utilise their synergistic effects. To accomplish this, we synthesized a random copolymer via reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymer was composed of methyl methacrylate and polyethylene glycol methacrylate-containing units. The polymer was functionalized with integrin- and syndecanbinding ligands. A blending technique was used to generate interfaces with ligand multivalency. Specifically, highly peptide-functionalized polymer chains were blended with non-functionalized polymers chains. Upon film casting, these generated surfaces displaying nano-scale islands of high peptide density due to the size and shape of the polymer random coils. Endothelial cells were cultured on these surfaces and their behaviours were investigated under static and flow conditions. Our results show that the biomaterials functionalized with multivalent integrin-binding ligands promote the formation of focal adhesions, improve endothelial cell adhesion, migration, and endothelialization rate compared to surfaces functionalized with random distribution of integrin-binding ligands. Additionally, the biomaterials functionalized with mixed population of multivalent integrin- and syndecan-binding ligands show additional improvement over surfaces with just multivalent integrinbinding or syndecan-binding ligands alone. Specifically, we observed synergistic improvement of endothelial cell adhesion, improved focal adhesion formation and cytoskeletal assembly, an increased rate of endothelialization, and regulation of migration speed. These surfaces also regulate a range of endothelial cell functions when the cells were exposed to laminar flow shear stress including increased spreading, larger and more abundant actin stress fibers, elongation and alignment in the direction of flow, increased capture of endothelial cells from flow, and robust attachment of cells under flow. These results demonstrate that bioengineered materials presenting nanoclusters of both integrin- and syndecan-binding ligands could be used for the development of next-generation biomedical devices, especially small-diameter vascular grafts.
Keywordsendothelialization; integrin clustering; blood compatibility; multivalent ligand; focal adhesion; ligand functionalization; biomimetic; co-receptor; mechanotransduction; cell scavanging
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