The synthesis and characterization of novel biomaterials from natural building blocks: Biomaterials research: Past, present, and future directions, and, Saccharide-derived polymers as protein resistant biomaterials, and, Saccharide-peptide copolymers for gene delivery applications, and, Saccharide-peptide copolymer hydrogels for extracellular scaffold design.

摘要

Chapter 1 of this dissertation reviews the past, present, and future directions of biomaterial research and application. A brief history of the origins of biomaterial use is followed by a more detailed description of contemporary biomaterials. Current and future directions of biomaterial research are then presented with attention given specifically to surface modified contemporary biomaterials, hydrogels in tissue engineering, and soluble biomaterials for gene therapy applications. These applications are further subdivided into the two major strategies for biomaterial development: naturally derived biopolymers or synthetic polymers as biomaterials. A brief introduction of our laboratory's goal to produce novel biomaterial structure from natural building blocks (including saccharides and peptides) is then presented.; Chapter 2 of this dissertation outlines our design of a series of saccharide-derived polymers including: two side-chain methylether polyesters, a side-chain methylether polyamide, and a partially hydroxylated side-chain methylether polyamide. Each of these polymers was synthesized by condensation polymerization. The two novel saccharide-derived side-chain methylether polyesters have excellent resistance toward non-specific protein adsorption as demonstrated by surface plasmon resonance. In addition, these polymers combine biodegradability and functionalizability, giving them high versatility and excellent potential for use in non-fouling applications. The low cytoxicity of this series of polymers indicates that they may be useful in biomaterial applications.; Chapter 3 of this dissertation describes the synthesis of a series of cationic saccharide-peptide copolymers for use as a new class of biomaterials. The most effective known cationic gene delivery systems, such as polyethylenimine (PEI) and poly-L-lysine (PLL), have a large degree of cytotoxicity limiting their usefulness in clinical applications. Using a ground-up approach we synthesized a class of carbohydrate-peptide derived polymers to be used as effective and safe gene carriers. These polymers are derived from benign and inexpensive saccharide and carbohydrate starting materials, and were designed to have little relative cationic charge density along the polymer chain, making them less liable to be cytotoxic entities. After electrophoretic mobility shift assays the polymers were shown to effectively complex plasmid DNA. Atomic force microscopy imaging showed the average polyplex size was between 50-200 nm in diameter, making them candidates for gene delivery vectors. Luciferase gene delivery assays then proved the polymers to be more effective than a PLL control in DNA transport to Cos-7 cells' nuclei. Cell viability testing then proved these polymers were far less cytotoxic than the PLL control, lending them the possibility of application in gene therapy. This research describes a class of polymers that are safe and effective for gene delivery with a highly adaptable structure for further optimization.; Chapter 4 of this dissertation describes the synthesis of a series of saccharide-peptide derived copolymers with varying side-chains for use as hydrogel extracellular matrices (ECMs) for tissue engineering applications. These polymers were designed to have various charges at physiological pH (neutral, zwitterionic, cationic, and anionic) and were screened first by aqueous solubility, then cross-linking properties, and finally by their capacity to allow cell growth on the hydrogel surface. We found that an anionic, glutamic acid-derived copolymer system combined high aqueous solubility, efficient cross-linking, and excellent cell growth capabilities. In a final attempt to control some aspect of cell behavior the hydrogel was functionatized with a cell adhesion ligand (RGD) which increased cell adhesion rates versus controls having no RGD.