Pharmacologically active materials for localized nitric oxide therapy
Masters, Kristyn Simcha
West, Jennifer L.
Doctor of Philosophy
Nitric oxide (NO) functions as a ubiquitous biological messenger and effector molecule. In humans, NO performs unique actions throughout the body; for example, NO may aid in the prevention of blood vessel re-occlusion, or restenosis, following angioplasty as well as improve dermal wound healing. However, due to the wide-ranging biological effects of NO, systemic NO therapy has the potential to create complications. NO-releasing hydrogel materials have been synthesized using biocompatible polymers in order to form tissue coatings to provide local and sustained NO therapy following vascular or dermal injury. These materials may be photopolymerized in situ to provide a conformal coating which is both protective and non-thrombogenic. Several copolymers of poly(ethylene)glycol (PEG) or poly(vinyl alcohol) (PVA) with NO donors have been synthesized to achieve NO delivery for periods of time ranging from hours to months. To understand the specific actions of NO in the process of restenosis, its effects on the adhesion, migration, and extracellular matrix elaboration of smooth muscle cells and endothelial cells have been investigated. Exposure of blood to NO-generating PEG hydrogels resulted in decreased platelet adhesion to thrombogenic surfaces. Additionally, smooth muscle cell growth was inhibited and endothelial cell growth stimulated in the presence of the PEG-NO hydrogels, thus indicating their potential for the prevention of restenosis. The synthetic agent YC-1 has been shown to potentiate the vasorelaxant and anti-platelet functions of NO. This compound maintained its activity following incorporation into PEG hydrogels, and successfully inhibited smooth muscle cell migration and platelet aggregation. Combination of YC-1 with an NO donor within hydrogels resulted in synergistic actions in the inhibition of smooth muscle cell proliferation. Lastly, NO-releasing PVA hydrogels have been used in vivo to enhance dermal wound healing in diabetic mouse model. Treatment with these hydrogels resulted in significantly increased wound collagen synthesis, thereby creating a more stable closed wound, which suggests that these materials may be useful for the treatment of chronic wounds. Due to their biocompatibility and ability to be photopolymerized in situ, the NO-releasing materials synthesized here have the potential for use in applications throughout the body where localized NO therapy is desired.
Biomedical engineering; Chemical engineering