Thermosensitive composite hydrogel with antibacterial, immunomodulatory, and osteogenic properties promotes periodontal bone regeneration via staged release of doxycycline and proanthocyanidin

Periodontitis is a common type of inflammatory bone loss induced by bacterial infection in tooth-supporting tissue. Effective bone regeneration in the inflammatory microenvironment of periodontitis remains challenging. Therefore, biomaterials with concurrent antibacterial and osteo-immunomodulatory properties are desirable to leverage the osteogenic potential of endogenous cells. In this work, we developed a thermosensitive composite hydrogel PF-127@DOX/ALG-MS@PA consisting of Pluronic F-127 (PF-127) and alginate microspheres (ALG-MS) that allowed the staged release of doxycycline (DOX) and proanthocyanidin (PA), with the aim to eradicate bacterial infection, cease inflammation, and ultimately promote bone regeneration. The composite hydrogel showed good dimensional flexibility in the liquid state and gelling capability at body temperature, which allows its functioning by local injection. In the drug delivery system, DOX showed burst-release profile to achieve excellent antibacterial property while the release of PA was relatively slow in the early stage and accelerated subsequently to reach a high concentration, thereby sequentially exerting immunomodulatory and pro-osteogenic effect. The composite hydrogel induced the M1-to-M2 transition of RAW264.7 and promoted osteogenesis of MC3T3-E1 cells in the inflammatory microenvironment. In a rat periodontitis model, the composited hydrogel lessened local inflammation and enhanced new bone formation in situ. The composite hydrogel that promotes periodontal bone regeneration in the inflammatory condition through programmed drug release is promising for periodontal therapy.