Sterilization and post-processing of bioresorbable polymers for cardiovascular stent applications

Abstract

Cardiovascular diseases are the leading cause of death globally and account for over 30% of deaths each year. Coronary artery disease, the disease of blood vessels supplying the heart, is the most common form of cardiovascular disease, and represents an increasing burden to healthcare worldwide. Bioresorbable polymer stents were developed with the aim of replacing traditional, permanent metallic stents as the gold standard of treatment for coronary artery disease by providing scaffolding to the vessel wall over a physiologically beneficial period, restoring the blood vessel to its natural state, and then degrading. However, the first generation of these implants was unable to meet clinical expectations due to design limitations and the inherent material property differences between bioresorbable polymers and traditional metallic alloys. Advancements in materials science and polymer processing, as well as a better understanding of how each manufacturing step influences final implant performance, must be achieved in order for future generations of bioresorbable stents to achieve clinical success. This thesis aimed to contribute to both of these areas by characterizing the influence of the terminal sterilization step on poly (L-lactide) (PLLA), the most commonly used bioresorbable polymer for stent applications, and by exploring electron beam treatment as a method of material property modification. Terminal sterilization is a processing step of interest as it is the final step prior to stent deployment, and can involve environmental conditions which may cause bioresorbable polymer degradation. Due to the strong property-processing relationship of these materials, any sterilization induced changes could undo strategic modifications made in earlier manufacturing steps. A parametric study was carried out to evaluate the effects of two commonly used sterilization techniques, electron beam and ethylene oxide, on the initial properties of medical grade PLLA. The suitability of vaporized hydrogen peroxide as a novel, alternative sterilization modality to ethylene oxide was also evaluated. Compression molded sheets of material were exposed to each technique over a range of doses, including those used for terminal sterilization. PLLA demonstrated a dose-dependent sensitivity to electron beam and experienced significant property changes within the terminal sterilization dose range. Ethylene oxide also influenced polymer properties, but had less of an overall impact than electron beam. Vaporized hydrogen peroxide demonstrated the highest level of compatibility across all doses tested, supporting its development for use with this material. Beyond sterilization, electron beam is also used as a controlled method of modifying polymer structure and properties through chain scission or crosslinking to tailor final material performance. Inducing an electron beam crosslinking response in PLLA could mitigate radiation-induced property degradation during sterilization and improve bioresorbable stent performance during deployment. Triallyl isocyanurate (TAIC) was selected as a polyfunctional monomer to promote radiation crosslinking and incorporated into PLLA at various weight percents using extrusion mixing. Compression molding and biaxial stretching work was then carried out to create flat sheets of material with the required sample thickness for e-beam processing. Samples were treated with electron beam and characterized to assess the resulting crosslinked material. Initial results showing changes in thermal properties indicated the presence of TAIC influenced polymer microstructure during biaxial stretching and that crosslinking may have occurred. However, no improvement in bulk mechanical properties was observed. Further analysis of the PLLA/TAIC material confirmed the presence of TAIC and that an e-beam dose and TAIC-concentration dependent e-beam crosslinking response was successfully induced. This may not have translated to observable changes to mechanical properties due to the formation of discontinuous crosslinked networks within the amorphous regions of the polymer rather than a continuous network throughout the material as a whole. In summary, this thesis generated knowledge in two areas key to the successful development of the next generation of bioresorbable stents. A comprehensive sterilization study of medical grade PLLA was carried out, addressing a gap in reported data to date and characterizing a novel sterilization technique of industry and regulatory interest. Feasibility work also demonstrated the potential of inducing an electron beam crosslinking response in PLLA and created an in-depth body of work which can be referenced when working with medical grade material or carrying out future projects in this area.