Cardiovascular biomaterials suffer from well-known problems associated with thrombosis and infection. The surface, or interface, of a biomaterial is one of the most important factors that determines its blood compatibility, or its ability to support growth and normal function of endothelial cells (EC). The proposed studies will focus on new interface materials designed to improve the host response to biomaterials. The objectives are to develop new biomimetic materials based on the central hypothesis that non-covalent physical forces created by a cell's glycocalyx provides the major determining factor in the adsorption and functional state of adsorbed proteins, that controls subsequent cell and molecular interactions. To test this hypothesis, we propose to investigate: (1) Biomimetic materials that mimick non- adhesive properties and anticoagulant functions of EC glycocalyx designed to achieve blood compatibility; and (2) biomimetic materials that mimick adhesive glycoproteins in the extracellular matrix (ECM) designed to facilitate endothelization. The biomimetic materials are designed to undergo irreversible assembly on a range of clinically- relevant biomaterials, and consist of surfactant polymers with pendant oligosaccharides, oligopeptides, and hydrophobic ligands. Surface modifications will be characterized by spectroscopic and physical methods, and atomic force microscopy that will permit nanoscale imaging and examination of intermolecular forces. EC-like anticoagulant functions will be achieved through pendant heparin oligosaccharides and bioactive oligopeptides derived from thrombomodulin. The effect of biomimetic modifications on interfacial properties and blood compatibility will be determined from spectroscopic, microscopic, and labeling measurements of protein and platelet-surface interactions under well-defined dynamic flow conditions. ECM-like biomimetic materials will incorporate bioactive oligopeptides derived from EC binding proteins and heparin binding oligopeptides from fibronectin. The adhesion, growth, migration, and shear stability of human ECs will be determined using a laminar flow system at physiologic shear stresses. Cell-surface interactions will be studied by analysis of actin stress fibers and focal adhesion proteins using confocal microscopy. From these studies, we shall determine the mechanisms by which alteration in interfacial properties affects adhesive plasma protein and platelet interactions, and how this correlates to blood compatibility or endothelization. If successful, this research will lead to highly effective biomimetic materials that combine protein resistance and anticoagulant functions; or facilitate stable endothelization.
| Zhu, Junmin (2010) Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering. Biomaterials 31:4639-56 |
