INTELLECTUAL MERIT: Nitric oxide (NO) releasing polymeric materials have shown great promise in enhancing the biocompatibility of implanted biomedical devices. S-nitrosothiols (RSNOs) are a class of NO-donor of great interest due to their presence in biological systems and their physiological role in the storage, transport and release of NO. Light is known to decompose RSNOs to release NO. The light mediated NO generation from these molecules provides a means of precisely controlling spatial and temporal delivery of NO in biomaterials applications. The intellectual merit of the proposed activities contained herein is to systematically develop novel RSNOs that have different substituents on aromatic thiol compounds such that stability and NO-release properties can be controlled. These novel NO-donors will then be appropriately entrapped in polymer matrices such that NO release can be controlled by using light as an external on/off trigger and no RSNO or parent thiol compound can leach form the polymer. These will be the first NO-releasing materials that can be applied to biomaterials research and development that offer the ability to variably control NO generation on-the-fly (increased intensity of light causes increased NO-release). The research proposed here will help increase our fundamental understanding of the behavior of RSNOs and develop potentially useful polymeric systems that generate NO locally to be used to actively mediate the biological response toward materials that are placed in contact with blood and tissue.
BROADER IMPACTS: The broader impacts resulting from this research will significantly further our understanding of what levels of NO are needed to impart desired physiological effects in specific tissues and what levels will cause damage to healthy tissue surrounding NO-releasing implants. This will be achieved by developing novel research tools that will allow quantitative information to be gained regarding how different cells respond to controlled surface fluxes of NO. This information will significantly increase our understanding of physiological roles of NO and lead to the intelligent design of NO-releasing biomaterials. Additionally, these tools will allow work to be undertaken that will begin to quantitatively correlate how cells respond to different surface fluxes generated in vitro and in vivo. There is a serious lack of ability to predict how new biomaterials will function in the complex and dynamic environment of the body. Materials that function beautifully in vitro often time fail when placed in vivo. Work contained within the proposal will develop a waveguide device upon which cells can be cultured that generates defined surface fluxes of NO with precise temporal and spatial control. This will allow quantitative in vitro cellular response to NO to be determined. Fiber optic probes that can generate precise surface fluxes of NO will also be developed that can then be inserted in vivo to correlate if identical surface fluxes cause identical cellular response in vitro and in vivo. Although detailed studies of cellular response to NO are not included in this specific proposal, the technology that will allow these studies to be undertaken will be developed within the scope of the proposed activities.
The objective of this research program is to begin the systematic development of nitric oxide (NO) donors that utilize light to trigger the release of NO. We developed the chemistries necessary to synthesize novel donor compounds that have different NO release properties. We then developed the methodologies to immobilize these compounds into 3 different polymeric materials (PVC, polyurethane and silicone rubber) and onto the surface of a polymer filler such that the NO-donors cannot leach from the polymer matrices. A wide variety of NO releasing materials can be made due to the addition of fillers and plasticizers to these materials as well as using different molecular weights of the base polymer, thus creating the ability to select NO releasing materials tailored to the needs of a specific application. It is envisioned that these materials could be applied as coatings on a wide variety of blood and tissue contacting devices in order improve their biocompatibility and ultimately to obtain more reliable and safer in vivo performance. Additionally, we propose to develop a novel system for cell culture studies that will be able to generate prescribed surface fluxes of NO such that quantitative information about how different cells respond to NO can be determined. In total, 4 PhD students, 2 MS students, 16 undergraduate students and 4 high school students have worked on research directly related to and supported by this project. The students each have ownership of a real aspect of the research project and make significant contributions to driving the project forward. This significantly contributes to training the next generation of scientists and engineers and enhances the overall educational experience of the students engaged in research. The students involved in this work have presented at a total of 23 local, regional, national and international conferences and 5 manuscripts have been submitted to peer review journals.
