PURPOSE:This study aimed to determine which treatment parameters of the SonoKnife device can be used to safely and effectively perform non-invasive thermal ablation of subcutaneous tissue. METHODS:A three-dimensional computational layered medium model was constructed to simulate thermal ablation treatment of the SonoKnife device. The acoustic and thermal fields were calculated with the Fast Object-Oriented C++ Ultrasound-Simulator software and a finite difference code, respectively. Subcutaneous tissue was represented as layers of skin, fat and muscle. The simulations were conducted for ultrasound frequencies of 1 or 3.5 MHz. The thermal dose model was used to predict the size and location of the ablated regions. The computer simulations were verified by using the SonoKnife to perform subcutaneous ablations in the neck area of healthy pigs, in vivo. Triphenyltetrazolium chloride viability stain was used to differentiate viable tissue from ablated regions ex vivo. RESULTS:The simulations for the layered medium model suggest that operating the SonoKnife at frequency of 1 MHz is more effective and safer than 3.5 MHz providing skin cooling is applied prior to ablation. These predictions were in agreement with the results observed in the animal studies. The required sonication time for ablation increased from 50 to 300 s by using 1 MHz. CONCLUSION:Our modelling and animal studies suggest that 1 MHz with pretreatment skin cooling are the optimal settings to operate the SonoKnife to safely and effectively perform subcutaneous thermal ablation of porcine skin. More work is needed to optimise skin cooling and define the optimal sonication time.