| dc.description.abstract | Cutaneous defects such as diabetic ulcers, severe burns, and traumatic injuries create a need for cost-effective wound care products that restore tissue function. This dissertation describes the development of an injectable polyurethane delivery system for therapeutic plasmid DNA that can fill deep tissue defects and promote regenerative healing. Injectable polyurethane scaffolds with robust mechanical properties, nontoxic reactants and degradation products, minimal reaction exotherm, and clinically relevant working and setting times were tested in rat and porcine excisional wound models. The polyurethane scaffolds were biocompatible and stented wounds at early time points, resulting in a reparative rather than a scarring phenotype at later time points. The number of macrophages was elevated in wounds treated with polyurethane scaffolds, which is consistent with a macrophage-mediated oxidative degradation mechanism. There were no significant differences between injectable and implantable scaffolds in wound contraction, scaffold degradation, cell proliferation, or apoptosis. These results provide evidence that applying polyurethane scaffolds by injection rather than implantation did not adversely affect the wound healing process or scaffold persistence.
Although injectable polyurethane scaffolds alone are not enough to accelerate wound healing, they have potential to deliver biologics to enhance healing. Delivery of plasmids encoding genes for regenerative factors is a promising approach to wound healing because plasmids are cheaper and easier to produce than proteins, and they lack the immunogenic risk associated with viruses. To stabilize plasmids during incorporation into polyurethane scaffolds, a library of novel diblock copolymers was developed. The lead candidate polymer formed polyplexes with plasmid DNA that achieved higher transfection and stability after lyophilization than polyethylenimine, a commonly used transfection reagent. These polyplexes transfected cells in vitro after incorporation into and release from polyurethane scaffolds. Overall, the results of this dissertation provide evidence that an injectable polyurethane delivery system for plasmid DNA has high potential for use in wound healing applications. | |
