Development and characterization of advanced nitric oxide-delivering polymeric systems against cardiovascular complications
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Valvular complications and atherosclerosis contribute to the majority of the cardiovascular disease related deaths worldwide. In this thesis project the role of normative tissue mineral concentrations in native and decellularized valves were studied in correlation with clinical patterns of acquired dystrophic calcification to understand the pathogenesis of the disease. Followed by development and characterization of nitric oxide (NO) delivery systems for the prevention of cardiovascular complications. Calcium concentrations were similar in aortic and pulmonary native leaflets, but 10-25% higher in the native pulmonary sinus (p=0.0018) and artery (p<0.0001) compared to analogous aortic structures. All native semilunar leaflets had higher phosphorus concentrations than their respective conduit tissues. No tripartite regional variations were observed. Decellularization did not reduce calcium in leaflets (p>0.05), but significantly removed wall and sinus calcium (p<0.05). However, 85% of phosphorus was removed from all valve tissues. Thus, the distribution of normal tissue calcium content is not inherently predictive of asymmetric anatomical patterns of clinical aortic valve degenerative calcification. Local delivery of NO through Poly(L-Lactic acid) (PLLA) matrix systems incorporated with poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing DETA NONOate were formulated for the prevention of valve complications. Similarly, S-nitrosoglutathione incorporated polycaprolactone (PCL) matrix system was developed for combating in-stent restenosis. PLLA matrices embedded with PLGA nanoparticles significantly reduced calcification rate (43% for 7 days; p<0.05) and alkaline phosphatase activity (97%; p<0.05) in valve interstitial cells. The cyclic guanosine monophosphate (cGMP) levels under osteoblastic conditions were significantly increased (139%; p<0.05), supporting that the anti-calcification activity of NO is mediated through NO-cGMP signaling pathway. NO releases from PLGA nanoparticles embedded PLLA matrix, prevented valvular calcification and inflammation without causing cytotoxicity. Stents coating conditions optimized using two level full factorial design predicted that PCL polymer with (17.5% w/v; +1) and (0.5% w/w; 0), polymer concentration and drug concentration, respectively displayed sustained and controlled drug release profiles, along with slow in vitro degradation profiles. Stents coated with NO releasing PCL matrix also inhibited platelet adhesion and activation. Hence, polymeric NO based delivery systems developed in this study provide promising new platforms for local sustained and controlled delivery of NO, significantly reducing cardiovascular complications.
Table of Contents
Valvular complications -- Calcium and phosphorus concentrations in native and decellularized semilunar valve tissues -- Cardiovascular effects of nitric oxide -- Bioprosthetic heart valve complications -- Advances polymeric matrix for valvular complications -- Atherosclerosis and restenosis -- Nitric oxide eluting cardiovascular stent against restenosis -- Summary and recommendations -- Appendix
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Ph.D.