Microstructured Chitosan-based Piezoelectric Sensor for Ultrasound-Driven Drug Delivery

Nanotechnologies can enable new therapeutic frontiers, contributing to the creation of drug delivery smart system that can release the drug in response to specific stimuli such as temperature, ultrasound, magnetic electric fields, pH of the microenvironment. These devices make it possible to improve the spatio-temporal control of the administration of the therapeutic agent, reducing side effects and preserving healthy organs and tissues. In this context, piezoelectric materials, able to convert mechanical energy into electric energy, represent an emerging technology to develop innovative platforms to drive the release of drugs and are attracting more and more interest. Among them, Chitosan is a biodegradable piezoelectric natural polymer with low environmental impact, high biocompatibility and, thus, with a great potential to develop the next generation of controlled drug delivery systems. The objective of the thesis project is to develop a wireless on-demand delivery device by combining ultrasonic stimulation with soft piezoelectric chitosan films with enhanced piezo-flexoelectric behavior loaded with drug molecules and capable of controlled release in response to mechanical stimulation. To obtain microstructured chitosan films with improved performances, a new manufacturing process was developed based on a solvent-casting soft lithography technique with a microstructured mold. The chitosan polymer film is fabricated with a protocol that includes solution preparation, degassing, mold surface preparation, vacuum-assisted solvent casting, neutralization, and drying. First, a microstructured Silicon mold was used. Wettability and surface study analyses were carried out on the patterned substrate. The combined use of PEDOT: PSS and degassing techniques proved to be fundamental for creating a defect-free microstructured chitosan polymer film. Then, with the aim of increasing the repeatability of the manufacturing process, a PDMS microstructured mold was used, designated ad hoc for the specific application, starting from a silicon master mold and a PMMA replica. This modification, significantly reduced the development time of the microstructured chitosan film and increased the scalability of the entire process. Electron and optical microscopy techniques and atomic force microscopy were used in this phase for surface morphology and topography studies. Gold and silver electrodes were then produced on the chitosan film for the fabrication of the final device. The electrical performance of the microstructured polymer film was measured using a custom-made setup for soft piezoelectric materials and compared with the electrical response of the flat film. This study demonstrated an increase in electrical performance and effective piezoelectric response, due to the presence of microstructures. The device was also prepared by loading Doxorubucin, a fluorescent anticancer drug, into the chitosan film to carry out the release studies under ultrasonic stimuli. The diffusion release rate of a sample without the application of ultrasound was compared with another sample subjected to intermittently activated ultrasound. From the result of cumulative Doxorubicin releases, in percentage, obtained via spectrofluorometer, it emerged that the microstructures favour better release control by ultrasound. Future work could focus on optimizing the manufacturing process of the device's electrodes, on optimizing the loading of the film with the drug, and to find the best stimulation conditions.