TY - JOUR TI - Design, fabrication, and characterization of bioactive amphiphilic polymers as cardiovascular therapeutics DO - https://doi.org/doi:10.7282/T3PC34J2 PY - 2016 AB - Recent advancements in cardiovascular drug-eluting stents (DES) have significantly improved clinical outcomes and survival rates in patients with arteries blocked by fat and cholesterol accumulation. Current DES utilize a cytotoxic or immunosuppressive agent to overcome earlier issues of restenosis, or smooth muscle cell (SMC) hyperproliferation, but the drugs and polymer overcoat are associated with an increased risk of late-stent thrombosis, or blood clot formation due to delayed re-endothelialization and hypersensitivity reactions. Both of these issues restrict blood flow and may cause angina, myocardial infarction, and/or death. An alternative therapeutic strategy is to target upstream events in the restenosis and thrombosis cascades, such as high levels of oxidative stress. In this research, bioactive micelles and nanoparticles were developed to minimize cellular interactions of oxidized low-density lipoprotein (oxLDL), which has been shown to induce excessive cellular proliferation and platelet activation. These formulations are comprised of amphiphilic macromolecules (AMs) containing a sugar-based hydrophobic domain and a hydrophilic poly(ethylene glycol) tail. The results indicate that when SMCs are exposed to high levels of oxidized lipid stimuli, AM nanoassemblies inhibited oxLDL uptake, downregulated scavenger receptor expression, and attenuated scavenger receptor gene transcription, and thus significantly suppressed SMC proliferation with minimal cytotoxicity. The potential for bioactive AM delivery was further evaluated as stent coatings, where AMs were self-assembled into monolayer coatings on metal oxide substrates using grafting-from and grafting-to approaches. In the grafting-from technique, molecules were polymerized from the surface in a multi-step synthesis, whereas polymers were pre-synthesized before end-functionalization to the surface in the grafting-to method. Densely packed layers of bioactive AMs gradually released from substrates, significantly suppressing SMC proliferation and platelet adsorption. Variations in the grafting method, functional end group, and linker length yielded a range of AM grafting densities, release rates, and reductions in SMC proliferation and platelet adsorption, suggesting that the bioactive AM release profile can be tuned to match physiological events in the restenosis and thrombosis cascades. Overall, the findings in this thesis highlight the potential of using AM formulations as stand-alone bioactive agents or for controlled therapeutic delivery from coronary stents to minimize restenosis and thrombosis. KW - Biomedical Engineering KW - Stents (Surgery) KW - Macromolecules LA - eng ER -