Tehran University of Medical Sciences Frontiers in Biomedical Technologies 2345-5837 10 3 2023 06 01 327 338 Pegah Khosravian 1- Medical Plant Research Center, Shahrekord University of Medical Science, Shahrekord, Iran Moosa Javdani Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran Melika Masoudi Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran Abdolnaser Mohebi Department of Clinical Sciences, Faculty of Veterinary Medicine, Shahrekord University, Shahrekord, Iran Amin Bigham Sadegh Department Clinical Sciences, Faculty of Veterinary Medicine, Shiraz University, Shiraz, Iran Abolfazl Barzegar 2. Resident of Theriogenology, Faculty of Veterinary Medicine, Shahid Chamran University, Ahvaz, Iran 2022 12 18 2023 01 14 Purpose: In this study, a controlled release drug delivery system loaded with piroxicam and methadone was synthesized and used subcutaneously in rat with experimental tibial defect and healing were assessed histopathologically. Materials and Methods: For this purpose 100 adult female rats were were randomly divided into five equal groups; group control, chitosan group, piroxicam group, methadone group, and piroxicam-methadone group. The morphological structure of the synthesized drug systems was studied by scanning electron microscope. In addition, the structure of the hydrogels was investigated by fourier transform infrared spectroscopy and while releasing the hydrogels gelation time, the release of piroxicam and methadone from the hydrogels were evaluated in vitro.   Results: Histological results of the 3rd day of the study showed the lowest extent and severity of inflammation in the chitosan, piroxicam, and piroxicam-methadone groups, while on the 7th day, tissue inflammation and the extent of bleeding was lower in the piroxicam, methadone, and piroxicam-methadone groups than in the other groups. Evaluation of new bone formation on day 21 showed that the chitosan, piroxicam, and methadone groups had better repair than the other groups. Conclusion: It seems that in the control group that did not receive any treatment intervention, following the experimental bone defect, the highest inflammatory response was observed in histological examination and finally the weakest bone repair. On the other hand, the presence of piroxicam, methadone and chitosan in the piroxicam-methadone group (all of which have anti-inflammatory effects) also seems to have a negative effect on repair. https://fbt.tums.ac.ir/index.php/fbt/article/view/619 https://fbt.tums.ac.ir/index.php/fbt/article/download/619/325