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.

中文翻译：

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具有抗菌、免疫调节和成骨特性的热敏复合水凝胶通过多西环素和原花青素的分阶段释放促进牙周骨再生

牙周炎是一种常见的炎症性骨质流失，由牙齿支持组织中的细菌感染引起。牙周炎炎症微环境中有效的骨再生仍然具有挑战性。因此，需要同时具有抗菌和骨免疫调节特性的生物材料来利用内源细胞的成骨潜力。在这项工作中，我们开发了一种热敏复合水凝胶 PF-127@DOX/ALG-MS@PA，由 Pluronic F-127 (PF-127) 和藻酸盐微球 (ALG-MS) 组成，可分级释放多西环素 (DOX)和原花青素（PA），旨在根除细菌感染，停止炎症，并最终促进骨再生。该复合水凝胶在液态下表现出良好的尺寸灵活性，在体温下具有凝胶化能力，这使得其可以通过局部注射发挥作用。在药物递送系统中，DOX表现出爆发释放特性，从而实现优异的抗菌性能，而PA的释放在早期相对缓慢，随后加速达到高浓度，从而依次发挥免疫调节和促成骨作用。复合水凝胶诱导RAW264.7从M1到M2的转变，并促进炎症微环境中MC3T3-E1细胞的成骨。在大鼠牙周炎模型中，复合水凝胶减轻了局部炎症并增强了原位新骨形成。通过程序性药物释放促进炎症条件下牙周骨再生的复合水凝胶在牙周治疗中具有广阔的前景。