The Effect of Kersen ( Muntingia calabura L .) Leaf Extract Nanogel on Stomatitis

Background: Recurrent aphthous stomatitis (RAS) is common painful mucosal condition affecting the 5%-60% world’s population and become the third largest oral disease in Indonesia. Despite their high prevalence, RAS treatment is currently still dominated by the use of chemicals that scientifically have adverse side effects. Therefore, it is necessary to develop new approach using herbal product with no side effects. This literature review summarizes the potential of kersen leaf extract (Muntingia calabura L.), its dosage forms, and the possibility using nanotechnology that can speed up the drug delivery process. Objective: to determine the possibility effect of nanoparticle cherry leaf extract in gel form on decreasing number of macrophages and stimulating collagen in stomatitis. Methods: literature search using the PRISMA method with Science Direct, PubMed, Scielo, NCBI, Research gate, and Google Scholar databases of 1107 articles with keywords “Muntingia calabura L. leaves extract”, “nanogel”, “flavonoid”, “quercetin”, “fisetin”, “macrophage”, “collagen”, “soft tissue healing process” and “recurrent aphthous stomatitis”. The results of the literature selection found 22 articles. Results: flavonoids in cherry leaf extract can reduce the number of macrophages and increase collagen stimulation. The mechanism of action begins by inhibiting the production of pro-inflammatory cytokines, inhibiting macrophage migration and adhesion, stimulating the production of growth factors by macrophages for collagen synthesis, and decreasing collagenase. Nano gel form may increase retention time and drug penetration. Conclusion: Nanogel based cherry leaf extract may reduce the number of macrophages and stimulating collagen in minor RAS.


INTRODUCTION
Dental and oral health is a very important aspect of a person's life. However, Indonesian people's awareness of the importance of maintaining dental and oral health is still low. This is consistent with the fact that there has been an increase in the prevalence of dental and oral diseases in Indonesia from 2013 to 2018 by 25.9% to 57.6% [1,2] . Recurrent aphthous stomatitis (RAS) is the third largest oral disease in Indonesia with a prevalence of 8%, reaching 5%-60% of the world's population [3] . The prevalence of RAS is very high in developing countries and 80% of people experience RAS before the age of 30 years [4] .
Recurrent aphthous stomatitis (RAS) is the most common ulcerated condition of the oral mucosa with characteristic round, painful ulcers, surrounded by a reddish area, and covered by a pseudomembrane [5]. The etiology of RAS is unknown, but it is associated with various predisposing factors such as a family history of RAS, mechanical trauma, hormonal imbalance, stress, food allergies, bacterial and viral infections, immunological factors, iron deficiency, nutrition, and smoking [6,7] . Management of RAS aims to reduce pain, speed healing, reduce the number and size of ulcers, and increase the disease-free period [8].
Drugs used for the treatment of RAS include topical anti-inflammatory steroids (Hydrocortisone hemisuccinate, Triamcinolone acetonide, and Betamethasone valerate), topical antiseptics (Chlorhexidine, Triclosan), topical non-steroidal anti-inflammatory drugs (Benzydamine Hydrochloride, Diclofenac) and systemic drugs (Tetracycline, Colchicine, Dapsone, thalidomide). Generally, RAS treatment uses topical steroids [9] . However, long-term and/or repeated use of steroid drugs have side effects such as adrenal suppression, candidiasis, and burning sensation, bad taste in the mouth, mucosal atrophy, nausea, sore throat, and xerostomia [10,11] . Currently, the use of herbal medicines is more widely developed because it has no side effects and 85% comes from plant extracts [12,13] . Therefore, the author wants to know the effect of herbal ingredients, namely cherry plants, on the healing of RAS.
Cherry plant is a flowering plant from the Elaeocarpaceae family which is widely found in tropical areas such as Malaysia, India, South America, Central America, and Indonesia [14] . Several studies have proven that the content in cherry leaves has anti-inflammatory and antioxidant activity [13,14,16] . Cherry leaves contain flavonoid compounds, tannins, triterpenes, saponins, and polyphenols with the highest flavonoid concentration of 70% [17] . The types of flavonoids found in cherry leaves include flavones, flavonols, flavans, and biflavans [18] . Flavonoids themselves are known as antiinflammatory and antioxidant bioactive substances that can accelerate the healing of RAS [19] .
Flavonoids are compounds with low solubility in water, very hydrophobic, and chemically unstable under physiological conditions. Flavonoids are very sensitive to environmental factors such as temperature, pH, and light. The low solubility causes limitations on the use of flavonoids and the acceptance of flavonoids as herbal medicines [20] . The most effective way of drug delivery for poorly soluble bioactive molecules such as flavonoids is to use nanoparticles. Nanoparticles have the highest drug loading efficiency and can protect flavonoids from degradation due to physiological conditions (especially due to endogenous enzyme activity) [20,21] . Flavonoids in cherry leaf extract can work optimally in treating recurrent aphthous stomatitis (RAS) if it is in the form of nanogels. Based on the problems above, the authors wanted to know the effect of cherry leaf extract (Muntingia calabura L.) on the reduction of the number of macrophages and stimulation of collagen as an alternative treatment for stomatitis based on nanogels.

PURPOSE
To determine the effect of cherry leaf extract nanogel on decreasing the number of

METHODS
The research design used is a systematic literature review (SLR) by using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) method. Systematic literature review is a research method to identify, evaluate and interpret all relevant research results related to certain research questions and topics [22] .
The journals used in the literature review were obtained through a database of international journal providers, namely Science Direct, PubMed, Scielo, NCBI, Research Gate, and Google Scholar. The relevant sources are then stored as a reference for selection. The keywords used for the journal search were "Muntingia calabura L. leaves extract", "nanogel", "flavonoid", "quercetin", "fisetin", "macrophage", "collagen", "soft tissue healing process" and "recurrent aphthous stomatitis". The data search was taken based on the inclusion criteria. The inclusion criteria in this literature review include literature that is included in the category of journal articles (original article), published in English, fully accessible, belongs to the health sciences group, published from 2011-2021, and must contain research data related to keywords

RESULTS
As shown in the image below (Figure 1), based on online search of the database, 1,107 articles were found. Furthermore, they were selected using the Preferred Reporting Items for Systematic Review and Meta Analyses (PRISMA) method. The final results of the selection were 22 literatures.

DISCUSSION
This literature review discusses the effect of cherry leaf extract (Muntingia calabura L.) as a nanogel-based topical drug on the treatment of Recurrent Aphthous Stomatitis (SAR) with variable number of macrophages and collagen stimulation. Recurrent aphthous stomatitis (RAS) is a common oral lesion with unclear etiology, but has predisposing factors such as stress and nutritional deficiency. In RAS patients there is an excessive inflammatory process. SAR treatment itself aims to reduce pain and speed up the healing process. Research Pandya et al. in 2017 showed that flavonoid compounds from herbal ingredients were able to provide analgesic, antibacterial, anti-inflammatory effects, and without side effects in patients with minor RAS [24] .
Cherry leaves through a maceration process with 70% and 96% ethanol solvents produced the highest amount of flavonoids. Types of flavonoid compounds in cherry leave include rutin, quercetin, and fisetin. However, the type of flavonoid compound that has the highest concentration is quercetin. The concentration of quercetin in cherry leaves reached 10.255% [25,18,26,27,28,29] .
Cherry leaf extract (Muntingia calabura L.) was then developed into nanoparticles and processed into a gel-based topical preparation. The application of nanotechnology in drug delivery aims to protect flavonoids from degradation due to oxidative and enzymatic environments. The gel preparation was chosen because it has advantages such as stabilizing the application of nanoparticles, prolonging drug contact time with the mucosa, increasing bioavailability, and providing a protective layer on the lesion from mechanical irritation and bacterial contamination [30,31,24] . Research by Karavana et al. in 2012 also proved that nanogel preparations increase retention time and penetration of bioactive ingredients to the mucosal surface thereby accelerating the healing process of RAS [32] .

Denta, Jurnal Kedokteran Gigi
The mechanism of action of flavonoids in suppressing excessive inflammation in RAS is by reducing the number of inflammatory cells such as macrophages, neutrophils, and lymphocytes, suppressing the production of proinflammatory cytokines (IL-6, IL-1, TNF-, NF-B), and reducing pro-inflammatory cytokines and release of reactive oxidative stress (ROS) by macrophages [28,33,34,35,36,37,38] . The research of Cui et al. in 2019 also explained the effect of flavonoids on macrophage activity including by inhibiting Nitric Oxide (NO) production, migration, and macrophage adhesion [39] . The mechanism of action of flavonoids in the wound healing process (ulcer) in RAS includes stimulating macrophages to produce growth factors (TGF-β, FGF-2, and VEGF) and reducing collagenase (MMP-9 and MMP-13). Increased TGF-will induce fibroblast cell proliferation and increase collagen synthesis, deposition, and maturation. Increased fibroblast growth factor (FGF-2) will increase the synthesis and formation of collagen. Increased vascular endothelial growth factor (VEGF) will stimulate angiogenesis so that it can induce the process of migration, proliferation, and differentiation of endothelial cells. Proliferation of capillary blood vessels is needed as an oxygen and nutrient pathway for tissue growth [35,40,41,31,42,43,44]

CONCLUSSION
Based on a literature review study that has been carried out by the authors of 22 journals, it can be concluded that the cherry leaf extract (Muntingia calabura L.) may has effect on healing minor type of recurrent aphthous stomatitis (RAS). This is because the content of flavonoids in cherry leaves as an antiinflammatory can reduce the number of macrophages and increase collagen synthesis. Further research in the laboratory is needed to determine the effectiveness of cherry leaf (Muntingia calabura L.) as a nanogel-based herbal medicine for recurrent aphthous stomatitis (RAS).