Effect of Topical Melatonin Application on Dental Implant Osseointegration and Marginal Bone Level (Clinical and Radiographic Evaluation)

Melatonin (N-acetyl-5-methoxy-tryptamine) is an indoleamine synthesized and secreted by the pineal gland and other organs, such as the retina, bone marrow, and intestines in a circadian pattern. Extrapineal sites contribute poorly, or only upon specific stimuli to circulating melatonin. Melatonin influences numerous physiological actions that may be mediated by the binding of the indoleamine to membrane receptors in all tissues. Because of its lipophilic properties, melatonin passes through cell membranes to gain access to subcellular organelles, being capable to bind to some cytosolic proteins like kinase-C . Currently, melatonin is not considered a hormone in the classical sense of the term, because it is synthesized in several organs and does not exert effects on a specific target , but it is rather a powerful cell protector against molecular damage. For the synthesis of melatonin, the pineal cells take up tryptophan from the blood and, through hydroxylation and a decarboxylation process, turn it into serotonin. Serotonin is then converted into N-acetylserotonin through N-acetyltransferase and subsequently methylated to the final form of melatonin by the enzyme hydroxy indole-O-methyltransferase . In healthy individuals, the maximum secretion of melatonin occurs between midnight and 2 a.m., then it decreases to a minimum during the day. Melatonin has numerous physiological functions in different parts of the body, such as the control of circadian rhythms \, regulation of body temperature, and activation of the immune system.In the oral cavity, melatonin has been recognized as an important substance with paracrine effects on nearby cells, it also acts as an antioxidant and an anti-inflammatory and plays an important role in bone formation and in the reduction of bone resorption.

Osseointegration defined as a direct connection between living bone tissues and a titanium implant without any connective tissues. Osteoblasts are bone formative cells, and osteoclasts are bone resorptive cells. When these cells work together physiologically, the formation and resorption processes of bone tissue is known as bone remodelling. The remodeling of bone tissues is regulated by the action of systemic hormones (estradiol, parathyroid, growth, and melatonin) and by the bone marrow and osteoid matrix-derived growth factors.Insufficient bone quality and quantity can be seen frequently in elderly populations with atrophic and osteoporotic bones, and this situation stems from increased osteoclastic activity due to a reduction in osteoblastogenesis. In addition, local free radical concentrations in all body cells, including osteoblasts, can reduce osteoblastic activity in aged patients. This process could lead to a reduction in bone regeneration capacity. Melatonin can also suppress osteoclastogenesis, and therefore inhibit bone tissue resorption. In addition to this, in vitro research has reported that melatonin can increase osteoblast proliferation and differentiation. So was proposed that the local application of melatonin during surgical implant placement procedures would be an effective treatment technique for dental implant osseointegration. Worthy osseointegration is a prerequisite for dental implants. Optimal osseointegration depends on the formation of new bone around implants, which may be stimulated by the application of biomimetic agents. Considering the bone metabolism, melatonin acts directly on the osteoclast, a multinucleated cell, which resorbs the extracellular matrix through various mechanisms, including the production of free radicals. Moreover, in pre-osteoblast cultures from rats, melatonin, in a dose-dependent manner, promoted the development of bone sialoprotein and other protein bone markers, including alkaline phosphatase, osteopontin, and osteocalcin, and speeds up their period of differentiation into osteoblasts from the normal rate, which is 21 days, to 12 days, this reaction is mediated by the membrane receptors for the indole. Also, melatonin, may interfere with the function of the osteoclast and thereby inhibit bone resorption. conducted an experimental study using melatonin with dental implants in dogs. Two weeks after implant insertion, melatonin significantly increased all parameters of osteointegration. It has been observed that melatonin, increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. These data point towards an osteogenic effect of melatonin that may be of clinical importance, as it could be used as a therapeutic agent in situations in which bone formation would be advantageous, such as in the treatment of fractures or of osteoporosis.

Toxicology of Melatonin:- The physiological functions of the pineal hormone melatonin are extremely diverse. The functions include direct and indirect modulations of anti-oxidative defense, blood pressure, body temperature, cortisol rhythm, reproduction and immune function . Correspondingly, exogenous melatonin has been investigated as a treatment for a number of medical and surgical diseases, demonstrating encouraging results . In the USA, melatonin is available as an over-the-counter non-prescription drug. In most European countries, however, melatonin remains a prescription drug (Circadin) and has only been approved as a treatment for primary insomnia in people over 55 years of age. However, a recent Norwegian register study documented a 3- to 5-times increase in off-label use among children and adolescents in the time period 2004 to 2012 . Melatonin is generally considered safe, but the increasing clinical use with potentially increasing doses necessitates further investigations of the risks of both mild and serious adverse effects.

Periotest M device:-

Periotest device was developed to measure the damping characteristics of natural teeth and has been used to evaluate implant. It was developed by Schulte in 1983 to quantify TM , and then utilized by Teerlinck et al , to measure implant stability and to overcome destructive methods in measuring the implant stability like histologic analysis, tensional test, push-out/pull-out test and removal torque analysis. The (Classic/Wired) Periotest device has been the subject of several studies with generally favorable results. These results showed that the Periotest device generally demonstrated a high degree of repeatability and reliability. A wireless version of the Periotest (Periotest "M") has been introduced to the profession. According to information provided by the electronic page of the Periotest M /wireless device manufacturer (Medizintechnik Gulden, Modautal, Germany), Periotest M is simpler to perform an objective evaluation of an implant's stability compared to classic Periotest. In Periotest M wireless design, the user can benefit from maximum freedom of movement. The device can be used for taking measurements on a wide variety of implants, without the need for any special accessories, such as a smart peg . The Periotest has an important advantage against the others like the Osstell device: it can be applied directly to the implant superstructure .