Abstract
The primary pathology of periodontitis involves the overactivated immune response triggered by bacterial infection, resulting in the progressive periodontal deterioration and bone loss. It has been proved that All-trans retinoic acid (ATRA) can attenuate the polarization of pro-inflammatory M1-type macrophages alongside promoting osteogenesis, but its therapeutic potential in periodontitis is still unclear. Meanwhile, due to its poor aqueous solubility and vulnerability, the application of ATRA for local administration remains limited. Here in this work, a nanoparticle-loaded immunomodulatory hydrogel with additional functions of both osteogenesis promotion and anti-bacteria was designed. Specifically, bioactive ATRA molecules were incorporated into zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (ATRA@ZIF-8) and then encapsulated in ε-poly-l-lysine (EPL) grafted gelatin methacryloyl (GelMA) hydrogel for convenience of local injection. The resulting ATRA@ZIF-8-loaded hydrogel (AZGE) exhibited remarkable capability in attenuating the M1-type polarization of RAW264.7 macrophages and facilitating the osteogenic differentiation of periodontal ligament cells (PDLCs). Additionally, benefiting from the EPL segment, the AZGE hydrogel displayed a prominent antimicrobial activity to inhibit the reproduction of Porphyromonas gingivalis. Furthermore, the therapeutic effect of the AZGE hydrogel on periodontitis control and periodontal tissue regeneration was ulteriorly confirmed with an experimental model of ligature-induced periodontitis. In summary, the versatile ATRA-derived injectable hydrogel provides a feasible treatment strategy for periodontitis via remodeling the local osteogenic immune microenvironment.
Published Version
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