Dissolvable microneedle patch enables local delivery of immunomodulatory microparticles containing bifunctional molecules for periodontal tissue regeneration

Abstract Periodontitis is initiated by dysbiosis of the oral microbiome. Pathogenic bacteria elicit ineffective immune responses, which damage surrounding tissues and lead to chronic inflammation. Although current treatments typically aim for microbial eradication, they fail to address the significance of immune cell reactions in disease progression. Here, we searched for small molecules as drug candidates and identified a bifunctional antibiotic, azithromycin (AZM), that not only inhibits bacterial growth but also modulates immune cells to suppress inflammation. We further engineered a dissolvable microneedle patch loaded with biodegradable microparticles for local and painless delivery of AZM to the gingival tissues. Inflammatory cytokines were decreased while anti-inflammatory cytokines and M2 macrophage were increased with AZM treatments in vitro. In vivo delivery of the AZM-loaded microneedle patch demonstrated the same effects on cytokine secretion and the promotion of tissue healing and bone regeneration. In addition, microparticles containing anti-inflammatory interleukin-4 alone or in combination with separately-formulated AZM microparticles, had similar or slightly enhanced therapeutic outcomes respectively. The bimodal action of AZM obviates the necessity for separate antibacterial and immunomodulatory agents, providing a practical and streamlined approach for clinical treatment. Our findings also demonstrate the therapeutic efficacy of microparticles delivery into the soft tissues by a minimally invasive and fast-degrading microneedle patch and offer a novel therapeutic approach for the treatment of periodontitis and other diseases through immunomodulation. Graphical Abstract