Postoperative administration of mesenchymal stem cells enhances peri-implant tissue healing in a medication-related osteonecrosis of the jaw model

Patients undergoing antiresorptive therapy are generally advised against dental surgical procedures, particularly implant placement, due to the high risk of medication-related osteonecrosis of the jaw (MRONJ). Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into multiple lineages; they also regulate immune responses and tissue repair. Previous studies have demonstrated that MSCs alleviate MRONJ symptoms and promote peri‑implant tissue healing, although their activation depends on specific in vivo conditions. In this study, we compared the effects of MSC administration before and after implantation on peri‑implant hard and soft tissue healing in a rat MRONJ model. In vivo, preoperative MSC treatment did not result in significant differences in peri‑implant bone or soft tissue healing compared with the drug-only group, whereas postoperative MSC treatment significantly improved multiple parameters; some reached levels comparable to those of controls. In vitro, postoperative MSC treatment modified the biological characteristics of primary oral epithelial cells and influenced the secretion of key reparative proteins. These findings suggest that postoperative MSC administration enhances peri‑implant tissue healing and modulates epithelial cell function, providing new experimental evidence for preventing and treating implant-associated MRONJ. STATEMENT OF SIGNIFICANCE: Medication-related osteonecrosis of the jaw (MRONJ) limits safe implant therapy in patients taking antiresorptive drugs. Using a reproducible MRONJ-like rat model, we show that postoperative, but not preoperative, mesenchymal stem cell (MSC) administration improves peri‑implant healing. Postoperative MSCs strengthen epithelial sealing, enhance angiogenesis, reduce neutrophil infiltration, and lessen necrotic bone, with congruent micro-CT and histology. We also report the first isolation and analysis of primary oral epithelial cells from MRONJ peri‑implant tissue, revealing MSC-driven gains in proliferation, survival, and barrier proteins. These findings identify therapeutic timing as a key design parameter for MSC-based interventions and provide translational guidance for mitigating implant-associated MRONJ risk, while informing broader biomaterials strategies that couple immunomodulation with repair of the epithelial-implant interface.