Identifying structure-property-processing relationships of tyrosol-derived polyarylates for the efficient design of biodegradable medical devices
Creators: name: Cohen, Jarrod
Publisher: name: No Publisher Supplied
Year: 2021

description: Polymeric biomaterials have revolutionized the medical sector, but acidic degradation byproducts, limited tunability, and non-degradability of those used in commercial products, has led to an unmet need for new, improved libraries of polymers. Specifically, the design of new materials with defined structure-property relationships will enable faster, and more efficient material selection for application specific research. Biomedical research intertwines itself between many scientific disciplines including chemistry, materials science, biology, engineering and medicine. Due to the complexity in designing new biomaterials, many research groups focus on incremental chemical or physical modifications to existing materials such as composites of metal alloys or synthetic polymers like poly(lactic acid) (PLA). To address limitations polymeric biomaterials, several laboratories have focused their efforts on developing new libraries based on amino acids for their improved biocompatibility and tunability. Tyrosine has had great translational success from the Kohn group into the clinic due to the structurally rigid aromatic ring and biocompatibility of the amino acid. Tyrosine has been successfully used by the Kohn lab to generate polycarbonates and polyarylates, which exhibit excellent biocompatibility and tunability. Slight modifications to these polymers including incorporation of hydrophilic oligomers of PEG or free acid groups led to a library of materials with predictable tunability. One major limitation of tyrosine-based polymers is the mismatch between degradation and resorption due to the presence of amide linkages, the degradation of which is limited to enzymatic modes. We hypothesize that to overcome this limitation, replacing the amide bond in the tyrosine diphenol with an ester derived from tyrosol will promote resorption while maintaining biocompatibility and tunability. Tyrosol is a naturally derived anti-oxidant commonly found in olive oil. A small subset of the library described in this dissertation have been previously used in 3D printing applications. However, the design of such polymers for broader biomedical applications has not been explored. Establishing structure property relationships within a library of tyrosol-derived polymers was a main thrust of this dissertation. We hypothesize that establishing these correlations will enable the more efficient design of polymers for specific application. Synthetic optimization of novel tyrosol diphenols and subsequent polymers followed by an intensive examination of polymer properties was carried out to identify the great potential of this library. Tyrosol derived poly(ester-arylate)s were explored with three major structural comparisons: (i) diphenol symmetry, (ii) diacid carbon chain length, and (iii) diacid bond rigidity. Resulting polymers were then characterized for their chemical, degradative, thermal, mechanical, and biological properties. Structure-property relationships were established to better guide material design. A wide range of material parameters were obtained and implications in polymer design identified. These design parameters were extended to specific processing techniques including additive manufacturing. Methods for improving bioinks used in additive manufacturing were explored through the use of click chemistry to further expand on the polymer properties of printed constructs using fused deposition modeling. Correlations between polymer molecular weight, printing parameters, and post printing curing times were identified. Additionally, these polymers were investigated for their use as drug eluting devices. A subset of the developed polymer library was chosen, and chemical modifications were made to the polymers in order to provide improved drug delivery for both hydrophobic and hydrophilic APIs. Extruded implantable devices loaded with drug were designed for applications including implantable birth control and treatments for HIV. Poor patient compliance is often a hurdle in improving clinical outcomes, and therefore, long acting implants can improve treatment effectiveness. Guided rationale based upon the known chemical properties of monomers was used to design an expanded library of poly(ester-arylate)s for a range of biomedical applications. Tunability of thermal, mechanical, and processing properties enables selection of a material for specific physiological applications, as different pathologies require materials to match their properties. This library has established a platform for developing versatile polymeric materials by biomolecular tethering to improve device properties, incorporation of peptides for improved biologically responsive degradation, and new resorbable nerve conduits.