Current Evidence on the Use of Curcumin in Modern Periodontology- A Narrative Review

Curcumin, the main bioactive ingredient in turmeric, has been used to treat multiple diseases and conditions due to its numerous health benefits and therapeutic effects. The properties of natural and chemically modified curcumin (CMC) have been extensively investigated, with strong evidence on its anti-inflammatory, anti-microbial (antibacterial, antiviral, antifungal properties), antioxidant, anti-angiogenic, anti-carcinogenic, antispasmodic, hepato-protective, and wound healing properties. The aim of this review aims to present an overview of the use of curcumin in periodontal therapy and the biological mechanisms behind its properties. Findings from in vitro studies suggest that curcumin can promote osteogenesis, down regulate proteases, promote wound healing, and suppress periodontal bacteria. Results from animal studies suggest the potential of curcumin to reduce periodontal inflammation and alveolar bone loss. Topical


Introduction
In line with more holistic approaches, there has also been increased interest in decreasing the chemical body burden, which can originate from the environment (air, water, soil, food, etc.), medications, and personal care products, among other sources [8]. Herbal and natural products play an important role in these integrative approaches, with turmeric having potent medicinal effects as a supplement and therapeutic agent for numerous diseases and conditions [5]. While herbal products are increasingly popular, their use should be based on scientific evidence. In this review, the scientific foundation for the use of curcumin in periodontology will be discussed.

Therapeutic Use of Curcumin in Medicine
A recent bibliometric analysis of the literature on curcumin found over 18,000 publications on the topic, including clinical and experimental research, in vitro studies, meta-analyses, and reviews, from which half were published after 2014. The majority of studies evaluated curcumin use in relation to cancer, inflammatory conditions, and oxidative stress. The overwhelming number of studies on this natural compound points to its promising therapeutic properties [9].
Several beneficial biological activities have been associated with curcumin, including anti-inflammatory, anti-microbial (antibacterial, antiviral, antifungal properties), antioxidant, anti-angiogenic, anticarcinogenic, antispasmodic, hepato-protective, and wound healing properties. It affects multiple signaling molecules and cellular activities. Therefore, it has been investigated for the treatment of a variety of inflammatory conditions and tumors, through in vitro, experimental, and clinical studies ( Table  1). In dentistry, curcumin has been evaluated for the treatment of oral mucosal lesions, oral cancer, and periodontal disease [10][11][12][13][14][15][16][17]5]. healthy volunteers who were administered 1 to 12 g in a single oral dose presented one of those side effects [25].
Synthetic analogs: Different CMC compounds have been formulated to change its diketone form into triketone form, improving the chemical properties such as zinc-binding, bioavailability, and therapeutic effects. Some analogs include difluorinated-curcumin (CDF), dimethoxycurcumin, compound 23, GO-Y039, CMC 2.24, and EF24. Pre-clinical studies suggest stronger inhibition of matrix metalloproteinases (MMPs) for CMC, as compared to its natural form [26].

Therapeutic Use of Curcumin in Periodontology In Vitro Studies
Multiple in vitro studies have reported the anti-inflammatory activity of curcumin and CMC. Studies on human periodontal ligament stem cells (hPDLSCs) exposed to curcumin report increased osteogenic cell differentiation and improved balance between MMPs and their tissue inhibitors [27,28]. Exposure of human gingival fibroblasts to curcumin enhanced wound healing when compared to CHX exposure [29]. Gingival tissues from periodontitis patients presented comparable MMP-9 decrease when exposed to curcumin or doxycycline [30]. The antimicrobial capacity of curcumin has also been reported in studies on periodontal bacteria, including Porphyromonas gingivalis (Pg), Aggregatibacter actynomycentencomitans (Aa), and Fusobacterium nucleatum (Fn). Even with concentration as low as 12 µg/ml, curcumin was able to decrease bacterial metabolic activity, adhesion and biofilm formation in vitro when used alone or as part of photodynamic therapy (PDT) [31][32][33][34][35][36][37]. In human gingival fibroblasts and macrophages exposed to Pg LPS, curcumin reduced inflammatory cytokines and cyclooxygenase-2 (COX-2) expression [34][35][36]38]. Hu et al. [39,40] have suggested the Nuclear factor-κB (NF-κB) pathway as another potential mechanism through which curcumin can affect the initial steps of periodontitis development [40].

Authors
Year Animal Model

Mode of Administration Results
Ghavimi et al. [ Curcumin inhibited inflammatory marker production and osteoclastogenesis, decreasing alveolar bone loss. In the study from Elburki et al. [54], oral administration of CMC 2.24 led to lower gingival levels of MMP and inflammatory cytokines, and reduced activation of NF-κB and p38 MAPK. In diabetic rats with periodontitis, CMC 2.24 reduced hyperglycemia, inflammation, and connective tissue destruction [54]. In a recent systematic review and meta-analysis on the use of curcumin in experimental periodontitis, Borges et al. [21] reported that oral administration of 30mg/kg/day of CMC for at least 15 days was able to reduce periodontal bone loss. When natural curcumin was used, the 30mg/kg/day dose did not affect bone loss while the 100mg/kg/day dose led to less bone destruction, as compared to the control group [21].
The mechanisms behind the anti-inflammatory effects of curcumin and CMC in experimental periodontitis includes decreased expression of MMPs, inflammatory cytokines, such as TNF-α, IL-6 and IL-1β mRNA in gingival tissues, and osteoclastogenesis markers, such as RANK and RANKL *44, 56,59].
While most experimental studies on periodontitis and curcumin used oral or gastric gavage, Hosadurga et al. [60] investigated the topical application of curcumin gel in experimental periodontitis in rats in comparison to placebo. Gingival inflammation and edema were significantly lower in the test group [60]. More recently, the use of a collagen curcumin membrane infused with aspirin and curcumin was tested on bone defects in dogs. In defects where the test membrane was used, there was an increase in osteogenesis when compared to defects covered with a commercial membrane. The authors suggested that the antimicrobial and anti-inflammatory properties of curcumin can improve the results of guided bone regeneration procedures [61].

Clinical Studies-Topical Curcumin
Topical application of curcumin has been evaluated as an adjunct to periodontal therapy for gingivitis and chronic periodontitis in the form of gel, mouthwash, irrigation solution, adhesive strip, sponge, and chip (Table 3). Curcumin gel has been the most studied delivery method in clinical periodontal studies .

Gel:
In studies comparing the application of curcumin gel to CHX gel in gingivitis patients (applied twice a day for 21 days), curcumin was at least as effective as CHX in improving plaque index, gingiva index, and bleeding on probing. Pulikkotil & Nath [62,63] assigned sixty volunteers with healthy gingiva to one of three groups: curcumin gel, CHX gel, or CHX/metronidazole (MTZ) gel. Participants did not perform any oral hygiene apart from the oral application of the gel twice a day for 10 minutes for the duration of the study (29 days). The curcumin group presented the lowest increase in GCF (IL-1β and chemokine ligand 28-CCL28), while the clinical variables were similar for all three groups. The authors concluded that the anti-inflammatory effect of curcumin gel was comparable to CHX-MTZ gel and superior to CHX gel [64].
The first study to investigate the use of sub-gingival curcumin gel as an adjunct to periodontitis treatment was published in 2011. Through a split-mouth design, control sites were subjected to Scaling and Root Planning (SRP) and 2% turmeric gel, while control sites were subjected to SRP alone [65]. Both groups exhibited improved outcomes for clinical parameters and trypsin-like enzyme activity, but greater reductions were observed in sites treated with curcumin gel. For pocket depth, test sites presented a 1.1 mm higher average reduction than control sites. Since then, numerous studies have further investigated the use of curcumin gel in periodontitis patients and the majority provides evidence of better clinical and microbiological outcomes when compared to placebo or SRP alone (Table 3) [65]. For the studies that provide a comparison between curcumin and CHX gel, curcumin gel performed equally or better than CHX [66][67][68].
Recently, the postoperative application of curcumin gel was compared to periodontal dressing application after flap surgery in twenty patients. Early wound healing and tissue response were similar in both groups, however, the curcumin group reported less use of analgesics after surgery [69]. Using a split-mouth design, Sreedar et al. [70] compared four groups: SRP, SRP + Curcumin gel, SRP + gel + PDT at day 0, SRP + gel + PDT at days 0, 7 and 21. Quadrants that were subjected to curcumin gel and photoactivation presented superior clinical results than SRP alone or combined with curcumin gel [70].
Muhammad (2020) [71] reported higher reduction of serum IL-1β, and TNF-α and increased serum levels of zinc and magnesium when SRP was combined with curcumin gel in chronic periodontitis patients [71].

Mouthwash:
In a randomized controlled trial of patients with moderate to severe gingivitis, one session of professional prophylaxis followed by twice-daily curcumin mouthwash use presented comparable results to CHX mouthwash for gingival and plaque index, when used for 14 and 28 days. These findings were supported by additional studies by additional gingivitis studies [72]. In addition to beneficial clinical results, Arunachalam et al. (2018) [75] also reported lower levels of salivary reactive oxygen metabolites (ROM) after use of curcumin oral rinse in gingivitis, which was not observed for CHX oral rinse [74,75].
In chronic periodontitis patients with rheumatoid arthritis, the effect of SRP alone or combined with CHX or curcumin/essential oils mouthwash was investigated. While the CHX group presented a higher reduction in PPD and CAL, only the curcumin group had improvement in markers of rheumatoid arthritis [76]. Clinical parameters showed a slight benefit of curcumin in relation to CHX after 3 months, however, after 6 months, greater pocket depth reduction was observed in the CHX group. There were no differences in the BANA microbiological test results during the study. The authors concluded that, due to the lower toxicity and fewer side effects, irrigation with a curcumin solution can be an adequate substitute for CHX solution. In the study from Perez-Pacheco et al. (2020) [77] nano curcumin particles were used as an irrigation solution during SRP for the treatment of periodontitis. When compared to a placebo, the curcumin group did not present any clinical nor microbiological benefit. In type 2 diabetic patients with residual periodontal pockets, the combination of SRP and PDT using curcumin and LED irradiation showed the most positive results when compared to SRP alone, combined with curcumin irrigation or LED irradiation after 3 months [78,79].
Strip: Postoperative use of a mucoadhesive curcumin strip was evaluated after periodontal surgery in 15 patients. In each patient, control sites received a placebo strip and test sites received the curcumin strip.
Healing was uneventful for all areas. After 7 days, significantly lesser pain was reported for sites that received the strip [80].
Sponge: A collagen sponge was tested for local drug delivery of curcumin in sites with pocket depth of 5 mm or more in sixty chronic periodontitis patients subjected to SRP. Control sites received CHX chips, and clinical and microbiological parameters were evaluated after 3 and 6 months. Greater results were observed for the CHX group, which can indicate the inefficacy of this delivery method for curcumin [81].
Chip: Local drug delivery using CHX or curcumin chip was compared to SRP alone in forty chronic periodontitis patients using a split-mouth design. After 3 months, CHX and curcumin sites exhibited superior clinical results, measured as plaque index, gingival index, pocket depth, and relative attachment level, with no differences between CHX and curcumin treatment [82]. Malekzadeh et al. (2020) [83] studied the effect of 80 mg curcumin capsules once a day or placebo on forty-eight patients who suffered from gingivitis or mild periodontitis. After 28 days, there was a statistically significant difference in papillary bleeding index (PBI), and modified gingival index (MGI), with better outcomes observed in the test group. After 4 weeks, all patients were subjected to SRP. In the absence of SRP, systemic curcumin presented positive effects of gingival bleeding and inflammation [83].

Clinical Studies-Systemic Curcumin
The effect of systemic curcumin as an adjunct to periodontal treatment in gingivitis patients was investigated by Kaur et al. [84] Sixty patients were enrolled and as randomly assigned to receive SRP or SRP combined with 350 mg of an antioxidant mixture containing curcumin, lycopene and piperine. Gingival clinical parameters were evaluated after 3 weeks and reduction in plaque index, gingival index and pocket depth were marginally higher in the test group, suggesting that adjuvant systemic antioxidants can help reduce gingival inflammation [84].

Anti-Inflammatory and Anti-Microbial Properties of Curcumin
In periodontology, the most relevant biologic activities of curcumin are related to its anti-inflammatory and antimicrobial properties. Multiple molecular mechanisms have been described to explain curcumin's anti-inflammatory actions, including: -Nuclear Factor Kappa (NF-κB): this protein plays a crucial role in the cellular and molecular signaling that takes place during several chronic inflammatory diseases, including periodontitis, rheumatoid arthritis, inflammatory bowel disease, and asthma. In in vitro experiments, exposure of cells to cytokines, microbial pathogens, or their products induces activation of NF-κB, which is suppressed by curcumin [85,86]. -Cyclooxygenase-2 (COX-2): this enzyme catalyzes the formation of prostaglandins, which are important mediators in the inflammatory response. Prostaglandins have been implicated in the pathogenesis of periodontitis and alveolar bone resorption. Curcumin has been demonstrated to inhibit COX-2 expression in vitro [87]. -Inducible nitric oxide synthase (iNOS): This enzyme is key for the production of nitric oxide and is regulated by NF-κB. Nitric oxide is an important signaling molecule that participates in the pathogenesis of inflammation in the lungs, joints, intestines, and gingiva [88]. Curcumin can promote degradation of iNOS and inhibit its synthesis [89]. -Vascular endothelial cell surface adhesion molecules: including E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). Expression of these adhesion proteins in the endothelium is mediatedby pro-inflammatory cytokines and NF-κB, resulting in the extravasation of leukocytes from the blood vessels into the tissues [90]. Curcumin down regulates expression of vascular adhesion proteins by inhibiting NF-κB [91]. -Cytokines: Curcumin has been demonstrated to regulate the expression of multiple proinflammatory cytokines, such as IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-18, and TNF-α. Those molecules are crucial components of the tissue destruction process in periodontal disease [92]. -AP-1 transcription factor: curcumin has been shown to inhibit this protein, which regulates a variety of cellular responses through gene expression, such as proliferation and apoptosis. Regulation of AP-1 indirectly affects the production of iNOS, cytokines, and matrix metalloproteinases (MMPs) [85]. -MMPs: these endopeptidases degrade extracellular and membrane components, including collagen, and mediate periodontal destruction. MMP-1, 3, 9, 14, and 13 secretion can be inhibited by curcumin [92].
-Anti-oxidant: curcumin is a potent scavenger for free radical compounds, including reactive oxygen species. It also inhibits the generation of free radicals and lipid peroxidation. These actions contribute to the reduction of oxidative stress [93]. -Cytoprotective proteins: the potential of curcumin to stimulate the expression of cytoprotective proteins, such as catalase, glutathiones, and superoxide dismutase, which indirectly decrease oxidative stress [93].
The anti-microbial activity of curcumin has been attributed to its effect reducing microbial cell division, inhibition of virulence factors, damage to the microbial membrane, prevention of microbial adhesion to host cells, and consequent reduction in biofilm formation [94]. Also, as a photosensitizer, when subjected to light irradiation, the resulting photo toxicity prevents microbial growth. A few in vitro studies evaluated PDT with curcumin and reported moderate to strong antimicrobial activity against Aa, Pg, and Fn [32,33,37,95]. However, evidence on the clinical benefits of curcumin PDT as an adjunct to periodontal treatment is scarce [79,96].

Take-Home Message
Findings from in vitro studies suggest that curcumin has the ability to promote osteogenesis, downregulate proteases, promote wound healing, and suppress periodontal bacteria. Findings from animal studies suggest the enormous potential of curcumin and its derivatives to contribute to mechanical periodontal treatment, as experimental inflammation and alveolar bone loss show remarkable reduction after curcumin treatment.
Despite the high number of clinical studies on the use of curcumin in periodontology, there are several missing points before curcumin can become part of the traditional treatment approach. The low toxicity, limited side effects, availability, low cost, and a full spectrum of beneficial biological properties are among the main advantages of curcumin. Results from most clinical trials suggest that the benefits of curcumin and CMC are at least comparable to CHX, but with fewer side effects and higher patient acceptance. In gingivitis, the use of mouthwash seems to provide the most efficient delivery of curcumin, whereas in periodontitis, the use of curcumin gel has been the most studied form. Currently, adjunctive PDT with curcumin does not seem to provide additional benefits to SRP, however, it can be beneficial in the treatment of smokers and patients who have systemic disease. Additional studies are warranted to shed light on substantivity, formulations, delivery, and doses. Curcumin analogs seem to present superior outcomes due to increased bioavailability and potency. For wound healing, the use of curcumin strips and gel shows good potential and should be further explored. Although still in its infancy, the use of membranes containing curcumin can open new possibilities for tissue regeneration in the future.
The anti-plaque, antioxidant and anti-inflammatory properties of curcumin are remarkable, however, the lack of robust scientific studies with larger samples and longer follow-ups currently hinders its clinical application. While the majority of pre-clinical and clinical studies on periodontal disease have investigated the topical application of curcumin, its potential to improve the host response when used as a nutritional supplement should not be ignored despite.

Conclusion
Curcumin, an ancient natural remedy and spice, has been extensively studied for its wide spectrum of health benefits, mainly related to the anti-microbial, anti-inflammatory, anti-oxidant, and anti-cancer properties. In periodontology, the benefits of curcumin topical use have been compared to those of chlorhexidine due to its potential to combat plaque, modulate the host response, decrease periodontal inflammation, and alveolar bone loss. Those properties have been widely confirmed in pre-clinical studies. The majority of clinical studies on the adjunctive use of curcumin in periodontal disease report superior clinical and microbiological results when compared to mechanical therapy alone. Nonetheless, there is a lack of randomized clinical trials with long-term follow-up and adequate sample size. Despite the major health benefits associated with systemic supplementation with curcumin, more studies are warranted in order to investigate its effectiveness in the management of periodontal disease. Lastly, curcumin analogs have improved the chemical structure of this polyphenol to improve its biological activity; however, its clinical application requires further scientific investigation.