Evaluation of pH responsive chitosan derivatives for localised "smart" drug release, using novel microfluidic devices

Localised "smart" drug delivery systems (LDDs) offer a promising strategy for infection control around implanted medical devices. In this study, seven pH-responsive chitosan derivatives were synthesized via functionalisation with zwitterionic or phenolic monomers (Amps, Sbma, Sba, and vanillin) and were assessed in terms of drug release under steady state and dynamic conditions. The materials were tested using a novel microfluidic platform designed to simulate key aspects of in vivo microenvironment by controlling flow rate, pH and liquid-to-sample ratios. The platform enabled the assessment of the materials in both steady-state and dynamic pH scenarios and allowed real time monitoring of the released drug concentration. Pharmacokinetic data revealed distinct burst and sustained release behaviours between homeostatic (pH 7.5) and infection-like (pH 5.5) environments for all the materials. To quantify the response (change in drug release) of the materials to consecutive pH stimuli, a new parameter (responsivity, Rs) was introduced and was used to assess their potential for smart drug delivery. Among all candidates, a vanillin-crosslinked blend (Va-blend) demonstrated the highest potential for smart release applications, combining low release at homeostasis but rapid and prolonged release under acidic conditions. Fine-tuning of polymer mass and drug loading further optimised release duration while, biocompatibility was confirmed through MTT assays and microfluidic bioreactor testing with aerobic bacteria and human periodontal ligament cells. The effective inhibition of bacteria was demonstrated in standard static conditions tests and bioreactor experiments. Overall, the developed materials, methodology, and tools presented here have significant potential to contribute to the advancement of more effective local drug delivery systems. By enabling precise evaluation of stimulus-responsive drug release under physiologically relevant dynamic conditions, the proposed microfluidic approach provides a powerful platform for accelerating the design and optimisation of next-generation smart biomaterials.