Polyesters from natural macrolactones for biomedical applications

Abstract

Enzymatic ring opening polymerization has become a widely used technique in the synthesis of biomedical polyesters. Many different copolymers based on all kinds of lactones were made during the last decade. In this study copolyesters based on unsaturated macrolactones are made using this technique. Changing the nature and the ratio of the comonomers and using the unsaturation to cross-link the polymers, the properties of the obtained polyesters were modified with the aim to develop a materials platform consisting of polyesters, which can be tuned for the right properties in an easy way. The applications focused on are suture materials and nerve repair. High molecular weight polypentadecalactone was synthesized via enzymatic ring opening polymerization using Novozym 435 as a catalyst. By scaling-up the process larger batches of polymer could be obtained. The mechanical and thermal properties of the products were determined. The obtained polymer was melt-spun into fibers, which were further elongated. Analysis of the fibers revealed differences in crystal orientation as a function of the processing and drawing conditions. Preliminary fiber tensile measurements confirm the highest strength for the fiber with the highest crystal orientation. A library was made based on the macrolactones globalide and ambrettolide, which are the unsaturated analogues of ?-pentadecalactone and 16-hexadecalactone, respectively. Polymerization was performed using Novozym 435 and all monomers could be polymerized to convenient molecular weights. Solubility of the unsaturated analogues is better in common solvents as compared to their saturated counterparts. Their crystallinity is still high, however melting and crystallization temperatures of the polymers obtained from ambrettolide and globalide are significantly lower than the corresponding values of their saturated analogues. All homopolymers were tested and proved to be non-cytotoxic. Hydrolytic as well as enzymatic degradation is very slow. By thermal and UV cross-linking via the main chain unsaturation, fully amorphous materials were obtained. However, degradation of these amorphous materials was still slow, what indicated that the high crystallinity is not the only property retarding the degradation. To investigate the influence of hydrophobicity and crystallinity on the material properties of these polyesters, and especially the degradation properties, random copolymers were made using small lactones like 4-methyl caprolactone, 1,5-dioxapan-2-one and 2-oxo-12-crown-4-ether as comonomers. All polymers were readily made, although copolymers containing 2-oxo-12-crown-4-ether only yielded low molecular weight products. All copolymers are proved to be non-cytotoxic, what makes these copolymers suitable for biomedical applications. By altering the amount of comonomer added to the reaction mixture, properties like hydrophilicity (by adding 1,5-dioxepan-2-one or 2-oxo-12-crown-4-ether) and crystallinity (by adding 4-methyl caprolactone) could be tuned. The incorporation of all monomers led to an increase in degradation rate of the polyesters, showing that both crystallinity and polarity are crucial for the degradation. The relation between the amount of comonomer added and the ability to form fully cross-linked polymers was investigated using a model system of e-caprolactone and globalide. It was found that only a small percentage of the used monomers needs to contain an unsaturation to be able to obtain complete network formation. Moreover, only a part of all double bonds is cured, which leaves opportunities to incorporate biologically active components via e.g. thiol-ene chemistry or other addition reactions. Next to utilizing enzymes as catalysts in the synthesis of polyesters, aluminum salen complexes with different phenolic substituents were explored for their catalytic activity towards polypentadecalactone synthesis. A clear influence of bulky substituents in the complex was observed, however the polymerization rates remained high. An unsubstituted aluminum salen complex was explored in the polymerization of lactones of different sizes. All lactones were polymerized to high conversions within a reasonable timescale. The smaller lactones polymerize fastest, followed by the large lactones. The middle-sized lactones react slowest, however still faster than ever reported before using a chemical catalyst different from ours. After synthesis of this library of different copolyesters, permeable scaffolds were aimed for using different porogens. To control the porosity of the material different ratios of porogen/polymer were investigated. After cross-linking the porogen is easily washed out using water. The cytotoxicity of the cross-linked scaffolds is low. In conclusion it can be stated that we were able to synthesize a complete library of novel biomedical polyesters based on unsaturated macrolactones which contains many different polymers suitable for different biomedical applications. The properties (degradation, strength etc.) of the products can easily be tuned to the specific needs for a specific biomedical application.