Hyperglycemia associated with diabetes mellitus is a significant risk factor for periodontitis and it polarizes the immune cells towards an inflammatory state. Specific biomaterials can deliver therapeutic or immunomodulatory agents to regulate the excessive periodontal inflammation. Dendritic cells (DCs) bridge the innate and adaptive immune systems and are crucially involved in periodontitis. Thus, targeting DCs is an attractive treatment option for diabetic periodontitis, which, by modulating the downstream adaptive immune cells could regulate the host immune responses. In this study, a chitosan-based thermosensitive injectable self-assembled hydrogel (TISH) was developed to modulate DCs towards a tolerogenic phenotype, which can induce regulatory T-cells to attenuate inflammation and promote healing. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and resveratrol were loaded into TISH (TISH(G + R)) and were sustainably released. TISH demonstrated good biocompatibility and cell penetration in its porous structure. DCs grown in TISH(G + R) under an in vitro hyperglycemic condition showed reduced maturation and activation markers such as CD80, CD83 and CD86, while simultaneously upregulated tolerogenic genes such as FOXP3, SOCS3, TGFß and IL10. Co-culture of these tolerogenic DCs with naïve T-cells induced regulatory T-cells differentiation, evidenced by elevated gene expressions of FOXP3, TGFβ and IL-10. In vivo subcutaneous injection of TISH (G + R) into the mice showed significant infiltration of DCs and regulatory T-cells. In conclusion, TISH was developed and optimized as an injectable hydrogel to modulate DCs towards the tolerogenic phenotype and induce regulatory T-cells under hyperglycemia. TISH has promising potential to improve periodontal parameters in diabetic periodontitis.
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