IADR Abstract Archives
Development of Preventive Therapy for Bisphosphonate-Related Osteonecrosis of the Jaw
Objectives: Bisphosphonate-related ONJ (BRONJ) often causing serious oral morbidity represents the largest population of antiresorptive agent-related osteonecrosis of the jaw (ARONJ). We found that BP adsorption to bone mineral was not permanent but establishes an equilibrium; and that BP can be replaced by a subsequent application of other BPs. The objective of this research was to develop a trans-oral epithelial formulation of low potency BP (lpBP) and to test the therapeutic efficacy for the prevention of BRONJ.
Methods: Florescent-lpBP was encapsulated in microfluidics-derived nanoparticles to develop deformable nano-scale vesicles (lpBP-DNV). The trans-oral epithelial drug delivery was examined using an in vitro human oral epithelial model (EpiGingival, MatTek Corp) and mouse maxilla in vivo. C57Bl6/J mice (female, 8-wo) were treated with a bolus IV injection of zoledronate. lpBP-DNV was topically applied on palatal gingiva once or twice, prior to the left maxillary first molar extraction. Two weeks after extraction, mouse maxillary tissues were harvested for standardized photography, microCT and decalcified histology.
Results: lpBP-DNV (170±10 nm diameter and +34±4 mV zeta potential) demonstrated the greater trans-oral epithelial delivery than without DNV in vitro. After a topical application, a fluorescent signal was detected on the underlining alveolar bone in vivo. Mice received a ZOL administration followed by tooth extraction led to ONJ-like lesions. By contrast, pre-treatment of lpBP-DNV eliminated alveolar bone exposure and reduced gingival swelling. MicroCT images demonstrated the delayed extraction socket healing in the BRONJ disease control group, whereas normalized socket healing was observed in the lpBP-DNV topical application groups.
Conclusions: This study developed an efficient and simple preventive therapy of BRONJ, which was applied prior to oral surgery in order to remove the adsorbed antiresorptive BP by replacing with lpBP. The topical application of lpBP-DNV drug formulation allowed a uniform distribution of lpBP on the alveolar bone, suggesting a highly translatable therapy in clinical dentistry.
Methods: Florescent-lpBP was encapsulated in microfluidics-derived nanoparticles to develop deformable nano-scale vesicles (lpBP-DNV). The trans-oral epithelial drug delivery was examined using an in vitro human oral epithelial model (EpiGingival, MatTek Corp) and mouse maxilla in vivo. C57Bl6/J mice (female, 8-wo) were treated with a bolus IV injection of zoledronate. lpBP-DNV was topically applied on palatal gingiva once or twice, prior to the left maxillary first molar extraction. Two weeks after extraction, mouse maxillary tissues were harvested for standardized photography, microCT and decalcified histology.
Results: lpBP-DNV (170±10 nm diameter and +34±4 mV zeta potential) demonstrated the greater trans-oral epithelial delivery than without DNV in vitro. After a topical application, a fluorescent signal was detected on the underlining alveolar bone in vivo. Mice received a ZOL administration followed by tooth extraction led to ONJ-like lesions. By contrast, pre-treatment of lpBP-DNV eliminated alveolar bone exposure and reduced gingival swelling. MicroCT images demonstrated the delayed extraction socket healing in the BRONJ disease control group, whereas normalized socket healing was observed in the lpBP-DNV topical application groups.
Conclusions: This study developed an efficient and simple preventive therapy of BRONJ, which was applied prior to oral surgery in order to remove the adsorbed antiresorptive BP by replacing with lpBP. The topical application of lpBP-DNV drug formulation allowed a uniform distribution of lpBP on the alveolar bone, suggesting a highly translatable therapy in clinical dentistry.