# Evaluation of the Effects of Locally Applied Resveratrol and Cigarette Smoking on Bone Healing
## 4 Discussion  
In this study, it was hypothesized that local application of low doses of RES in hydrogel would increase its efficacy on bone healing in CS and the damage caused by CS in bone healing could be prevented. For this purpose, a critical size defect model was used in the rat femur. The results of the study revealed that local application of low-dose RES with controlled drug release systems increased new bone area, vascularization, osteoblast numbers, and microscopic bone filling rates, similar to repeated applications of systemic high doses. CS affects bone metabolism due to its inhibitory effects on osteoblast activity, osteogenesis, and angiogenesis [29]. CS inhibits osteoblastic cells and causes changes in bone metabolism by changing parathyroid hormone levels, disrupting the absorption of vitamin D and calcium, and causing a decrease in bone mass by increasing cortisol levels [30]. It has been observed that CS impairs healing in bone fractures and increases the risk of complications that may occur after the operation [31]. It has also been reported to reduce the tensile strength of healing bone [32; 33]. Studies have reported that RES prevents bone resorption that occurs as a result of increased osteoclast activity due to inflammatory mediator release [18]. RES has been reported to increase bone mineral density, ossification amount, BMP proteins, and osteopontin levels [19; 20; 21]. [PERSON] et al. [34], in a study conducted with a periodontitis model they created in rats, injected 5 mg/kg daily subcutaneous RES into rats and reported that inflammatory mediators and osteoclast formation decreased and bone mineral density increased by the end of the experiment. Polymeric controlled delivery systems ensure that the drug remains within the therapeutic concentration range in a single dose while releasing it in a local area of the body, keeping the systemic drug level at a minimum and increasing patient comfort by facilitating patient monitoring [23; 35]. In this study, based on the knowledge that the negative effects of smoking on bone healing can be improved by systemically administered RES, it was thought that the same effect could be achieved by local application of lower doses of RES. For this purpose, Wistar rats were exposed to CS for one month. At the end of one month, a critical size defect was created in the femur. In the RES groups, RES was applied locally to the defect, and the CS groups continued to be exposed to CS for one month after the operation until the day the experiment was terminated. [PERSON] et al. evaluated the healing of tooth extraction sockets in rats that were exposed to CS twice a day for two months before the surgical operation, and they found that smoking negatively affected the early and late healing components of the extraction socket, especially the formation of granulation tissue and new bone trabeculae [36]. In a clinical study on smoking patients, [PERSON] et al. radiographically examined changes in the extraction socket and alveolar ridge dimensions after tooth extraction [37]. They reported that only in the smoking group was there a significant decrease in alveolar bone width, bone density at the center of the extraction socket, and bone density at the apical part of the socket before extraction. [PERSON] [38] investigated the long-term effect of chronic CS on periodontal bone height and reported that bone height decreased 2.7 times more in smokers than in