Biocompatible copolymers for localized cardiovascular drug delivery and tissue engineering
Taite, Lakeshia J.
West, Jennifer L.
Doctor of Philosophy thesis
The integration of bioactive and biomimetic signals into materials for drug delivery and tissue engineering serves to improve cellular responses and therefore healing by more closely resembling the natural cellular microenvironment. The materials developed in this thesis show promise in delivering therapeutic doses of nitric oxide (NO) to physiological systems and provide novel surfaces for the study of cell adhesion and spatial organization. NO has several biological functions that make it an ideal candidate therapeutic agent for the prevention of the occlusive scarring of blood vessels following treatment of coronary artery disease through procedures such as balloon angioplasty and bypass grafting. The present work incorporates NO donors into polymeric biomaterials, resulting in copolymers that release NO over controllable time frames depending on material design. These NO-generating polymers have proven effective in significantly reducing platelet adhesion and smooth muscle cell proliferation in vitro. Endothelial cells exposed to these materials displayed enhanced proliferation, which is essential in restoring vessel function. Local, sustained release of NO from perivascularly-applied hydrogels reduced unwanted neointimal formation by approximately 90% in an experimental balloon angioplasty model. Novel NO releasing dendrimers have been synthesized to establish the potential for injectible NO therapy and can be targeted to sites of active vascular disease. NO-releasing polyurethane has been synthesized as a candidate material for vascular grafts. The superior mechanical properties of polyurethane combined with the inhibition of platelet adhesion by NO promise increased patency in small diameter vascular prostheses. Bioactive poly(ethylene glycol) (PEG) hydrogels have also been synthesized with covalently bound cell adhesion moieties to elucidate the mechanisms of immune cell adhesion to the vascular wall under shear. Leukocytes perfused over the surfaces of these hydrogels in a parallel plate flow chamber display rolling and adhesion properties like those seen on vascular endothelium in vivo. This work also presents a system of patterning bioactive regions onto hydrogels using transparency masks. This system allows the formation of complex patterns of cell-adhesive regions that closely mimic in vivo cellular arrangement. The intrinsic biocompatibility of PEG and the decreased thrombogenicity that NO affords make these materials ideal for incorporation into blood contacting devices.