## 3 Polyphenols as Potential Agents in TMD
### Potential Polyphenols Application in TMJ Inflammation, In Vivo Studies  
Interesting data come from several _in vivo_ studies that validate data reported above and support the potential preventive and therapeutic roles of polyphenols in TMJ-related inflammation. The effect of curcumin administration on OA patients has been evaluated by several clinical studies, showing that curcumin could represent an ideal candidate in the management of pain and inflammatory state related OA [106]. Concentrations used in clinical trials are within a range of 180-2000 mg daily, in a period of treatment from 4 weeks to 8 months. For example, it has been reported that oral administration of turmeric extracts (1500 mg daily) for 4 weeks can significantly reduce pain in 367 primary knee OA patients, showing a comparable effect to ibuprofen (1200 mg daily), with a reduction of gastrointestinal side effects [107]. Significant improvement in clinical symptoms of OA in curcuminoid-treated subjects has been also shown in a randomized clinical trial in which 40 subjectswith mild-to-moderate degree knee OA received pure curcuminoids (1500 mg daily, three doses) or placebo for 6 weeks [108]. Anyway, regardless of the promising results, these data must be carefully considered because most clinical trials present limitations such as the limited number of patients and the high dosages of curcumin employed [109]. The vehicle systems used for therapeutic applications are mainly lipid nanoparticles, micelles, polymeric nanoparticles, liposomes, and emulsions. To make an example, there is evidence provided that the phytosome complex (Meriva(r)), composed of curcumin and phosphatidylcholine (1:2), improves oral absorption of curcumin, ameliorating symptoms and joint function in OA patients, as evaluated by Western Ontario and McMaster Universities scores [110]. It has also been shown that oral administration of curcumin-based oil-water nanoemulsions, obtained by the high-pressure homogenizing method, strongly reduces the levels of TNF-\(\alpha\) and IL-1\(\beta\) in both synovial fluid and blood serum on adjuvant-induced arthritis in rats [111]. In addition, also the role of resveratrol in preventing cartilage degradation and improving pain-related inflammation has been supported by _in vivo_ studies. For example, a randomized control trial has evidenced an improvement of pain gravity and a significant reduction of serum levels of the biochemical inflammation markers, such as TNF-\(\alpha\), IL-1\(\beta\), IL-6, after resveratrol administration (500 mg daily) to patients with knee OA [112]. The interesting results obtained in patients with mild to moderate radiological evidence of knee OA should also be highlighted, where resveratrol (500 mg daily) was used as an adjuvant in association to meloxicam therapy (15 mg daily) for 90 days and patients had improved pain, compared to the placebo [112]. The anti-arthritic effect of EGCG-glucosamine-casein-based nanoparticles has also been evaluated (1:2:8, w/w/w) on rats, resulting in histopathological changes in the joint cartilage with reduced inflammatory cell infiltration, synovial hyperplasia, and cartilage destruction [113]. The major challenge in the application of polyphenols is their poor absorption and low systemic bioavailability after oral intake, mainly related to their poor water solubility and high metabolism and clearance rate. These limitations must be critically considered, indicating the bio-transformation of polyphenols that occur during their uptake across the gastrointestinal system, liver, and finally in the peripheral tissue cells. Hence, following the oral intake, these compounds become substrates of phase I and phase II enzymes and are conjugated to methyl and sulfate groups and glucuronic acid in the small intestine and liver [114]. Further transformations are performed by the intestinal microflora enzymes leading to the formation of phenolic acids that undergo liver metabolism. These chemical changes modify the polyphenol structures and could alter their biological effects.