# Evaluation of the Effects of Locally Applied Resveratrol and Cigarette Smoking on Bone Healing
## 1 Introduction  
Ossecous healing is a multifaceted process influenced by both local and systemic factors. The success of oral surgical procedures is compromised by delays in bone healing. Studies have reported that cigarette smoking delays bone healing and, thus, disrupts surgical planning and success. In fact, it has been found to adversely affect osteogenesis by causing changes in testosterone hormones, calciotropic hormone metabolism, adrenal cortical hormone metabolism, the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), the receptor activator of NF-kB (RANK), the soluble decoy receptor osteoprotegerin (OPG) system, collagen metabolism, and bone angiogenesis [1, 2, 3, 4].  
Cigarette smoke (CS) is an aerosol with about 1010 particles per ml of carbonaceous polymeric material containing heavy metals, polycyclic aromatic hydrocarbons,N-nitrosamines, and various other organic chemicals. Tobacco smoke contains approximately 3500 chemical compounds, many of which are toxic, carcinogenic, or mutagenic (e.g., benzene, cadmium, benzopyrene, etc.) [5]. Thus, it can cause high levels of free radical formation, which can then increase bone resorption and reduce bone mass [5], potentially leading to osteoporosis.  
Many studies have been conducted on various vitamins, hormones, and antioxidant substances, such as vitamins C, E, and D, to reduce the effects of CS on bone turnover [6; 7; 8].  
Studies have shown that resveratrol (RES), an antioxidant substance, inhibits osteoclast formation while increasing osteoblast differentiation [9; 10]. RES (trans-3,4,5-trihydroxysilbene), a natural polyphenol, is found in the seeds of red grapes. It has been found to have osteogenic, antioxidant, anti-inflammatory, analgesic, and anti-aging effects and has also been shown to have regenerative potential [11; 12; 13; 14]. Studies in the literature have reported that RES inhibits osteoclast and bone resorption, increases osteoblast, and stimulates vitamin D receptor expression in osteoblast precursor cells in bone marrow [15; 16; 17]. Due to its anti-inflammatory properties, it has been reported that RES prevents bone resorption due to increased osteoclast activity as a result of the release of inflammatory mediators and that it increases bone mineral density, ossification amount, bone morphogenetic proteins ( BMPs), and osteopontin levels [18; 19; 20; 21]. [PERSON] et al. and [PERSON] et al. reported that RES increased osteoblast formation by directly affecting the NO/cGMP signaling pathway of estrogen receptors. It was also found to increase osteoblastic differentiation and inhibit RANKL-induced osteoclast differentiation and bone resorption [17; 22].  
In conventional drug applications, it is necessary to use high and repeated doses to increase the therapeutic effects. To eliminate these problems and negative effects in conventional drug applications, serious studies have been carried out in recent years on the use of controlled drug delivery systems. In these controlled delivery systems, the drug reaches the cells and tissues in the required doses over a long period [23]. Another advantage is that it can be safely and naturally eliminated from the body, so there is no need to remove the drug carrier system after drug release [24; 25]. Pluronic F-127 was chosen as a release matrix because of its unique properties as well as its ease of application to drug-polymer complexes in vivo [26; 27].  
The present study aimed to investigate the effects of CS and locally applied RES on bone healing histomorphometrically and to evaluate the effects of RES applied locally with a controlled delivery system on the negative effects of CS.