Investigating novel approaches to stimulate oral soft tissue repair in medication-related osteonecrosis of the jaw

Medication-related osteonecrosis of the jaw (MRONJ) is characterised by exposed necrotic bone with persistent mucosal wounds in the oral cavity. The disease is found in patients receiving bisphosphonates for the treatment of osteoporosis, myeloma and bone metastasis. The current management of MRONJ remains challenging as existing therapies have inconsistent outcomes, are often ineffective and are unable to resolve the disease. Novel approaches, including geranylgeraniol (GGOH) and platelet-rich fibrin (PRF), have been introduced as potential solutions to enhance the healing of MRONJ wounds caused by bisphosphonate toxicity. However, the biological effects of these methods on oral soft tissue healing are yet to be fully understood. The aim of this study was to evaluate the effects of GGOH and PRF, in particular a liquid-based, injectable formulation of PRF (I-PRF), on the behaviour of oral mucosa cells. We used two- (2D) and three-dimensional (3D) in vitro oral mucosa models to replicate MRONJ-like conditions. Zoledronate (ZA) and pamidronate (PA), the two bisphosphonates most commonly associated with MRONJ development, were used to induce oral mucosa toxicity as seen in MRONJ. Our results revealed that both interventions produced some improvements in cellular activities linked to the healing process. A limited range of GGOH concentrations were able to reduce bisphosphonate toxicity in oral fibroblast, but were ineffective in keratinocytes. Combined treatment of GGOH and bisphosphonates led to a reduction of metabolic activity of oral mucosa cells. I-PRF was shown to be biocompatible and demonstrated some positive effects on oral mucosal healing in the presence of bisphosphonates. I-PRF was shown to enhance cell proliferation and migration. I-PRF also partially protected the epithelial integrity of 3D oral mucosa models from ZA toxicity. We identified factors within I-PRF and suggest the potential role of these paracrine factors in mediating the cellular responses observed in this study. The data presented here showed how cells from the oral mucosa responded to GGOH and I-PRF in vitro. These findings also demonstrated GGOH is unsuitable for the treatment of MRONJ given the narrow range of therapeutic concentrations and associated toxicity. In contrast results from this study highlighted the potential of I-PRF to support soft tissue repair in MRONJ treatment.