Synthesis of Antimicrobial Oligomers and Their Related Polymers Using a Combination of Antibiotics for Dental Restorations and Adhesive Materials

Despite having limited longevity in the oral cavity, resin composites are the most widely used dental restorative material. Secondary caries, which is the recurrence of cavities at the tooth and restoration interface, is currently responsible for more than half of resin composite replacements. The inherent vulnerability of the resin chemistry to hydrolysis and the presence of esterase activity in the oral environment, in combination with polymerization shrinkage and mechanical loading, sets the stage for a compromised interface. Micro-leakage of bacteria into the marginal site between the tooth and restorative material facilitates the recurrence of caries at the interface. To overcome this challenge, the objective of this thesis was to synthesize, purify, and chemically characterize novel dimethacrylate oligomers with antibiotics covalently incorporated into the oligomeric structure using well-defined biodegradable moieties. The antibiotics Ciprofloxacin (CF) and Metronidazole (MN) were selected as a proof-of concept, and the molecular structure of these oligomers were conceived such as to stabilize the oligomer’s esters as a first line of defense against bacteria, while permitting the use of in-situ methacrylate polymerization chemistry for use in dental adhesive systems. Two dimethacrylate oligomers were synthesized, referred to as HLH-CFPEG and HLH-MN, with the former containing CF and the latter MN. In the presence of enzyme, both drug oligomers were significantly more stable when compared to the commercial monomer 2,2-bis[4(2-hydroxy-3-methacryloxypropoxy)-phenyl]propane (BisGMA). Upon degradation, both drug oligomers released their respective original drugs (CF or MN) differentially in free form. Polymer synthesis of resin formulations containing 15 wt% HLH-CFPEG or HLH-MN showed high gel content values (≥97%), and under hydrolytic conditions showed a continuous release of CF and MN during a 28-day monitoring study period. Drug oligomers co-polymerized with BisGMA and 2-hydroxyethyl methacrylate (HEMA) were not cytotoxic against human gingival fibroblasts. The antimicrobial adhesives demonstrated bonding to dentin, with no significant difference in the interfacial fracture toughness (KIC) values from the in-house formulated control composed of BisGMA and HEMA in the 2-step adhesive application technique. When a 3-step application was used, the in-house control had a small but significantly higher KIC value in comparison to the antimicrobial formulations.Ph.D