AIM & HYPOTHESIS: We hypothesized that the piezoelectric knife increases bone remodeling. The effect of a piezotome 2 prototype with different puissance and modulation settings on bone biology was compared under different bone resorption and/or bone formation conditions using an ex-vivo live bone organ culture MATERIALS & METHODS: We utilized an ex-vivo mouse calvarial bone culture system a n d piezocision surgical techniques with variable puissance and modulation settings under conditions of static versus dynamic, and formation versus resorption in order to decipher cellular, molecular, biological and genetic perturbations induced by piezocision surgery. In addition, we tested its impact on calvarial bone organ cultures in the presence of drugs such as bisphosphonate (zolendronic acid, ZOL) and insulin or its impact on bone healing with bone graft material such as Enamel matrix derivative (Emdogain). RESULTS: The impact of the piezoelectric knife extends beyond the immediate site of mineralized bone defect/damage. The impact is ~6 times greater than the apparent initial mineralized bone injury, 1.6 mm2, and extends to immediate surrounding local periosteal and endosteal cell layers, 11 mm2, leaving the mineralized bone layer intact. There were also major differences between the static and dynamic model systems in bone defect viii healing, resorption and new bone formation. There are also differences between the piezoelectric knife and bur in bone resorption and formation models and in both treated before or at the same time of the injury with bisphosphonate. In the calvarial defect repair model the defect closed much faster with the piezoelectric knife than with the bur. In a comparative study with controls versus piezotome or bur, and piezotome versus bur complete genomic analysis of changes revealed a large number of major differences in genomic expression levels. CONCLUSION: The extended effect of piezocision on the surrounding bone lining cells of the bone defect including de-vitalization of the proximal osteocytes within the intact mineralized bone matrix thet primes the bone to undergo rapid turnover. Piezocision incorporates high-frequency vibrational energy that can be transmitted a significant distance within the mineral phase and exploits the inherent bone cellular response mechanism(s) as defined by the global genearray analysis. / 2020-06-13T00:00:00Z