## 4 Discussion
First, smoking interferes with the function of lymphocytes, leukocytes, macrophages and increases the level of various proinflammatory mediators, such as TNF- \(\alpha\), IL-6, and C-reactive protein [27; 28]. Second, smoking decreases the fibroblast migration to the periapical wound area and stimulates the function of osteocl cells, which encourage bone resorption [29]. Third, smoking causes morphological alteration in the microvasculature, which in turn disturbs the oxygen and nutrient supply to the periapical wound area [30]. In the current study, a positive trend of healing was observed in nonsmokers (84.6%). This finding conforms to [PERSON] et al. [8] and [PERSON] et al. [31], who found a statistically significant association between smoking and periapical healing. On the other hand, [PERSON] et al. [32] and [PERSON] et al. [33] reported no significant difference in periapical periodontitis between smokers and nonsmokers. The presence of preoperative pain and swelling or sinus tract may also govern the outcome of periapical surgery as indicated by many studies. [PERSON] et al. [20] revealed that the presence of preoperative signs and symptoms discourages healing. They postulated that the healing potential of surgical wounds could be significantly affected by the stage of infection at the time of surgery, which is influenced by preoperative pain and signs. Similarly, [PERSON] et al. [22] also claimed a lower success rate in patients with pretreatment pain. Contrastingly, the present study did not find any difference in the healing success rate in relation to the presence of preoperative pain, similarly to [PERSON] et al. [34] and [PERSON] et al. [35]. The reason for there being no relation between the presence of preoperative pain and periapical healing after surgical endodontic treatment may be due to the fact that same treatment protocol was used for every patient and all treatment procedures were performed by the principal investigator. Another important prognostic factor in periapical healing is the size of the lesion. In the present study, 100% successful healing was observed in patients with preoperative lesions of less than 6 mm, while 45% healing success was evident in patients with more than 6 mm of preoperative lesion size. A large number of studies have described the favorable prognosis after periapical surgery in patients with preoperative lesions of less than 5 mm in diameter [20; 26; 34]. Alternatively, [PERSON] et al. [23] found an 80% success rate in periapical lesions of less than 10 mm in size at the time of surgery, compared to 53% success in periapical lesions of more than 10 mm in size. Multiple systemic diseases are known to interfere with periapical healing, such as diabetes, hypertension, osteoporosis, or any uncontrolled systemic disease. Hyperglycemia increases the level of inflammatory markers and influences the various functions of the patient immune system [36]. Similarly, hypertension is associated with alterations in response and differentiation of bone cells at various levels [21]. Moreover, the drug bisphosphonate is commonly used for the treatment and prevention of osteoporosis and it is well-established that it reduces bone remodeling [37], therefore patients with these systemic diseases were excluded from this study, in addition to the patients with a pre-existing medical condition such as pregnancy and lactating mothers. Further prospective studies are required to evaluate postoperative healing in relation to the presence of different chronic systemic diseases using microsurgical techniques. The findings of the study must be seen in light of some limitations. First, periapical surgery was performed by the conventional approach rather than microsurgical. The microsurgical approach offers numerous benefits such as small osteotomy, easy identification of root apices, visualization of minor anatomical variations, and preservation of cortical bone and root length by nearly 90-degree root resection.