Development of drug-releasing shape-memory polyurethane/hydroxyapatite composites - smart biomaterial for bone tissue implants

摘要

Introduction: Shape-memory polymers (SMPs) are mechanically active or smart materials, which can be deformed and fixed in a temporary shape and are able to return to their original, permanent shape when exposed to a suitable external stimulus. The unique attributes of shape memory effect in conjunction with biodegradability and drug delivery present enormous opportunities for the design of next generation, resorbable less invasive self-fitting medical implants, tissue scaffolds and medical devices. The ultimate goal of the study is to develop self - deploying drug delivery system for bone tissue regeneration utilizing thermoplastic SMPs which could self-fitting to a target tissue defect and ensure a local drug release at the site of administration. Materials and Methods: Hydroxyapatite/polyurethane (HA/PU) composites were synthesized through in-situ polymerization with biodegradable hydroxyl terminated oligomers of polycaprolactone and poly(lactide-co-glycolide), 1,6-hexamethylene diisocyanate as a coupling agent and dibutyltin dilaurate as the catalyst. HA nanoparticles (Merck) and gentamicin sulfate (GS) (5% wt.) ultrasonically dispersed in dehydrated tetrahydrofuran (THF) were added to synthesis mixture. Chemical structure of the composites were analysed by Raman spectroscopy. Drug release study were performed in vitro in PBS and analyzed using UV spectrophotometer at a wavelength of 332 nm. Shape memory behavior was analyzed in thermomechanical test by dynamic mechanical analyzer (DMA) in water. The shape recovery ratio Rr and the fixity ratio Rf were calculated based on DMA measurement. The relationship between amounts of HA, drug content and shape memory properties were analyzed. Results and Discussion: A series of thermoplastic nano-HA/PU/GS composite with the content of HA in the range 3,510 wt. % were synthesized. Quantitative assessment of the shape memory performance through thermomechanical shape memory cycles verified that all materials exhibited a shape-fixing ratio R_f from 80% to 85% and shape recovery ratio (R_r 80-100%). The best shape recovery ability R_f -100% in water at 37°C was observed for composite with 3% wt. of HA. The shape recovery ratio decreased slightly with an increment in HA nanoparticles weight fraction, due to formation of agglomerates that could be a hindrance in recovery of the macromolecule structure. In order to evaluate the effect of shape recovery on drug release profile the drug release study were performed for the samples subjected thermomechanical shape memory cycle. The results revealed sustained drug release over two weeks. However, initial burst release increased with increasing of HA weight fraction what could be connected with easier water penetration into polymer matrix through HA nanoparticles polymer matrix interface. Conclusion: We successfully prepared series of thermoplastic PU/HA composites based on biodegradable oligoesters combining controlled drug release and shape memory effect. All the drug-loaded samples have satisfactory shape memory properties with shape recovery within body relevant temperature, and drug release behavior, therefore appear to be potentially useful for biomedical applications.