The revolutionary role of tissue adhesives in wound closure, tissue sealing, and bleeding control necessitates the development of multifunctional materials capable of effective and scarless healing. In contrast to the use of traditionally utilized toxic oxidative crosslinking initiators (exemplified by sodium periodate and silver nitrate), herein, the natural polyphenolic compound tannic acid (TA) was used to achieve near instantaneous (<25s), hydrogen bond mediated gelation of citrate-based mussel-inspired bioadhesives combining anti-oxidant, anti-inflammatory, and antimicrobial activities (3A-TCMBAs). The resulting materials were self-healing and possessed low swelling ratios (<60%) as well as considerable mechanical strength (up to ∼1.0 MPa), elasticity (elongation ∼2700%), and adhesion (up to 40 kPa). The 3A-TCMBAs showed strong in vitro and in vivo anti-oxidant ability, favorable cytocompatibility and cell migration, as well as photothermal antimicrobial activity against both Staphylococcus aureus and Escherichia coli (>90% bacterial death upon near-infrared (NIR) irradiation). In vivo evaluation in both an infected full-thickness skin wound model and a rat skin incision model demonstrated that 3A-TCMBAs + NIR treatment could promote wound closure and collagen deposition and improve the collagen I/III ratio on wound sites while simultaneously inhibiting the expression of pro-inflammatory cytokines. Further, phased angiogenesis was observed via promotion in the early wound closure phases followed by inhibition and triggering of degradation & remodeling of the extracellular matrix (ECM) in the late stage (supported by phased CD31 (platelet endothelial cell adhesion molecule-1) PDGF (platelet-derived growth factor) and VEGF (vascular endothelial growth factor) expression as well as elevated matrix metalloprotein-9 (MMP-9) expression on day 21), resulting in scarless wound healing. The significant convergence of material and bioactive properties elucidated above warrant further exploration of 3A-TCMBAs as a significant, new class of bioadhesive.

The therapy of chronic periodontitis poses a perennial challenge due to its intricate etiology, specific bacterial involvement, and the presence of an inflammatory immune microenvironment. The misuse of antibiotics not only triggers bacterial resistance but also disrupts the balance of oral microbiota, exacerbating the host's inflammatory response. Herein, a novel integrated synergistic hydrogel delivery platform (named GM/OHA-GZN&M) was designed to facilitate rapid, non-invasive, and antibiotic-free periodontitis treatment. This injectable hydrogel delivery platform fulfils three distinct roles: as a subgingival plaque disruptor, immune microenvironment remodeler, and microbiome modulator. As a subgingival plaque disruptor, GM/OHA-GZN&M hydrogel effectively disrupted bacterial membrane homeostasis, depolarized it, and induced the leakage of materials in the membrane. As an immune microenvironment remodeler, it effectively mediates the targeted clearance of mitochondrial reactive oxygen species (mtROS) through polyphenols, restores mitochondrial function, and disrupts the free radical cycle of inflammation. As a microbiome modulator, it effectively suppressed pathogenic bacterial overgrowth, restored oral gingival microbiota balance in rats, and created a favorable subgingival microenvironment for periodontitis treatment. In in vivo experiments, the GM/OHA-GZN&M hydrogel was used to treat a periodontitis model established by silk thread ligation in rats. Histological, microbiological, and biochemical analyses demonstrated that the hydrogel could significantly suppress inflammation and effectively promote alveolar bone regeneration through immunomodulation. To sum up, this study presents a supports therapeutic potential approach for managing periodontitis.