1-1. Periodontitis
1-1-1 Pathogenesis and progression of periodontitis
Chronic periodontitis (CP) is a disease, which is prevalent in adults, with slow to moderate rate of progression (Armitage, 1999, Armitage, 2004). According to the The National Health and Nutrition Examination Surveys (NHANES III), ampng dentate persons aged 30 years and older, about 35% had CP to various extents (Albandar, 2002).
Features of CP include signs and symptons such as recession of the gingival margin loss of alveolar bone increased tooth mobility eventually exfoliation of teeth(Becker et al., 1979).
Destruciton of periodontium were resulted from perturbation of the balance between periodontal pathogens and host immune system. Endotoxin and collagenase secreted by periodontal pathogens will stimulate local inflammatory reaction and activation of host immue system. Inflammatory cells produces proinflammatory cytokine prostaglandin metalloproteinases (Cochran, 2008) to exacerbate imflammatory reaction and tissue destruction with clinical features of gingival bleeding formation of periodontal pockets(Frank, 1980).
Dental plaque was constituted mainly by bacteria. Different species of bacteria will connect to each other by means of various mechanisms. Coaggregation is a kind of
cell-to-cell recognition of genetically distinct cell types by the function of adhesins (Kolenbrander and London, 1993). Eventually, these bacteria will adherent to each other and/or to surfaces or interfaces, namely biofilm (Costerton, 1995). The complex biofilm can protect obligate anaerobes from the toxic effects of oxygen, and these anaerobic bacteria can form endotoxins to damage host tissue (Bradshaw et al., 1996). Within a couple of weeks, a matured biofilm with 50~100 µm in thickness, forms plaque (Lamont and Jenkinson, 1998). Calculus is formed by calcifying plaque with calcium and phosphorus ions. (Caton and Quinones, 1991). More and more plaque can be adhered to calculus, ends up with a vicious cycle (Page Rc Fau - Schroeder and Schroeder, 1976).
1-1-2 Treatment of periodontitis
Treatment of periodontitis is characterized by four phases: (1) Phase I therapy or cause-related therapy or non-surgical periodontal therapy. Objective of phase I therapy is to alter or eliminate the microbial etiology and factors that contribute to periodontal diseases by enhance oral hygiene, remove plaque and calculus, root planing, and elimination of local factors such as dental caries, ill-fitting prosthesis, excessive occlusal force (Nyman and Lindhe, 1979, Axelsson P Fau - Lindhe and Lindhe). (2) Phase II therapy or surgical periodontal therapy. Aims of surgical therapy include reduction or elimination of periodontal pockets, remove subgingival calculus in
intrabony defect or furcation area (Caffesse et al., 1986b), recontouring of irregular bone, tooth, or soft tissue, and regenerate bone by regenerative materials (Barrington, 1981). (3) Phase III therapy or restorative therapy. In this phase prosthetic
reconstruction is performed. (4) phase IV therapyor supportive periodontal therapy (Renvert and Persson, 2004). Patients are placed on a schedule of periodic recall visit after phase I therapy is completed for maintenance care to prevent recurrence of the periodontal disease.
1-2. Non-surgical therapy
Non-surgical therapy involves various means to control the infection causing
pathologic lesions in the periodontal tissues. Debridement, scaling, and root planing can alter the subgingival ecology through disruptionof the microbial biofilm, reduction of the amount of bacteria, and suppression of the inflammation (Lindhe et al., 2003).
Non-surgical periodontal treatment may be carried out using various types of instrument, including hand instruments, sonic and ultrasonic instruments, and ablative laser devices. The use of hand instruments allows good tactile sensation, but tends to be time consuming and requires correct and frequentinstrument sharpening (Lindhe et al., 2003). Sonic devices use air pressure to create mechanical vibration that in turn causes the instrument tip to vibrate, the frequencies of vibration ranging from 2000 to 6000 Hz (Gankerseer and Walmsley, 1987, Shah et al., 1994). Ultrasonic instruments convert
electrical current into mechanical energy in the form of high-frequency vibrations, the frequencies of vibration ranging from 18000 to 45000 Hz. In comparison to hand instrumentation, the use of sonic and ultrasonic instruments may provide better access to deep pockets and furcation areas(Kocher et al., 1998, Beuchat et al., 2001). Ablative laser therapy has bactericidal and detoxification effects, is capable of removing bacterial biofilm and calculus with extremely low mechanical stress and no formation of a smear layer on root surfaces, and can remove the epithelium lining and inflamed tissue within the periodontal pocket (Ishikawa et al., 2009, Mizutani et al., 2016).
Mechanical therapy comprised of meticulous debridement of root surfaces, scaling, and root planing had proven to be the gold standard for non-surgical periodontal therapy (Lindhe et al., 2003). Its efficacy is well documented in several systematic reviews (Suvan 2005; Tunkel et al. 2002; Van der Weijden and Timmerman 2002) by gains in clinical attachment levels (CAL), reductions in probing pocket depth (PPD) and frequency of inflammation. Maintenance phase of periodontal therapyis required after scaling and root planing (SRP) to prevent the recurrence of disease progression. It could also keep the good result of active treatment. However, residual pocketmay still exist during maintenance. The residual pocket may be related to difficulty of thorough debridement, such as sites with initial deep PPD(Rabbani et al., 1981) or anatomical structures(Caffesse et al., 1986a)(e.g. : developmental grooves, fossae, furcation area,
root concavities), which may hinder complete removal of calculus. Therefore, concept of adjunctive periodontal therapy have been developed: Systemically administered or locally delivered antimicrobial agents (Slots and Rams, 1990, Goodson, 1994,
Winkelhoff et al., 1996, Mombelli et al., 2011), Laser-assisted periodontal therapy(Aoki et al., 2015, Mizutani et al., 2016), and antimicrobial photodynamic therapy
(Christodoulides et al., 2008, Chondros et al., 2009, Lulic et al., 2009).
Systemically administered antimicrobial agents are dominated by antibiotics, it may be capable of eliminating periodontal pathogens, diminishing periodontal inflammation, and reducing possibility of recurrent periodontal disease (Goodson, 1994, Winkelhoff et al., 1996). However, systemic antibiotic therapy also has some disadvanages : possible antimicrobial resistance, sustained opportunistic pathogen, and general discomfort like gastrointestinal disturbances or nausea (Helovuo, 1987). In contrast, locally deliverd antibiotics can avoid development of antimicrobial resistance and accomplish 100 fold higher therapeutic doses in subgingival sites than those possible by systemic therapy (Baker Pj Fau - Evans et al., 1985). Its shortcomings include difficult of applying the therapeutic agents to deeper parts of the periodontal pocket and relatively
time-consuming if many periodontal sites have to be treated (Slots and Rams, 1990).
This study is focused on locally delivered antimicrobial agents as adjunctive periodontoal therapy.
1-3. Local drug delivery
Due to limited volume of periodontal pockets (Binder et al., 1987) and the rapid turn over of gingival crevicular fluid within the periodontal pocket (Goodson, 1989), it is imperative for locally delivered antimicrobials to reach their target sites and be maintained there long enough to achieve sufficient concentration (Goodson, 1989, Goodson, 1996). Therefore, more and more vehicles have been developed in order to consistently release drug at a level high enough to eliminate microbials for longer duration (Joshi et al., 2016).
All the locally delivered antimicrobial agents used in the involved articles in this study will be introduced briefly in this section.
1-3-1 Tetracycline fiber
A small-diameter cellulose-acetate hollow fibers were filled with tetracycline and put into periodontal pocket (Goodson et al., 1979). The composition of fibers had been modified by using ethylene vinyl actate as vehicle, with brand name of Actisite (ALZA Corp. CA). Actisite contains 25 % tetracycline, can be maintained in gingival crevicular fluid for over 10 days with sustained concentration of 1590 µg/mL, is the most widely used controlled-release tetracycline antimicrobial product (Goodson et al., 1983, Tonetti et al., 1990). However, additional fiber replacement or removal procedure is needed due to the non-resorbable characteristic (Goodson et al., 1991). Side effects including
gingival swelling, redness, or candidiasis infection have been reported
(Vandekerckhove et al., 1997b, Yalcin et al., 1998). Researches using tetracycline fiber as an adjunctive treatment in this network meta-analysis are: (Kinane and Radvar, 1999, Wong et al., 1998, Radvar et al., 1996, Newman et al., 1994b)
1-3-2 Doxycycline gel
Atrigel(Atridox, Atrix Lab), is a gel with 10% Doxycycline in the formation. It is a controlled-release antimicrobial agent, which can maintained 250 mg/mL concentration 7 days after injected into periodontal pockets (Polson et al., 1997). The gel had been approved by US Food and Drug Administration (FDA) with brandname of Atridox (Block Drug Corp. USA, 8.5% Doxycycline). Researches using doxycycline gel as an adjunctive treatment in this network meta-analysis are: (Salvi et al., 2002), (Bogren et al., 2008), (Tonetti et al., 2012).
1-3-3 Minocycline gel
Periocline (Sunstar. Japan) Dentomycin(Cyanamid Int. USA), is a gel which contains 2% minocycline. Its concentration in gingival crevicualr fluid 1 hour after topical delivered into periodontal pocket is measured 1000 µg/ml, and is measured 100 µg/ml after 48 hours, both above its minimal inhibitory concentration (MIC) (Satomi et al., 1987, Steenberghe et al., 1999). Researches using minocycline gel as an adjunctive
treatment in this network meta-analysis are: (Kinane and Radvar, 1999), (Radvar et al., 1996).
1-3-4 Minocycline microsphere
Arestin(OraPharma. USA) Minocin(Cyanamid Int. USA), is a bioabsorbable polymer microencapsulating minocycline hydrochloridein it. The resulting
microspheres are administered in powder form into periodontal pockets. Immediate upon contact with moisture, the polymer begins to hydrolyze and release minocycline.
Sustained release of the antibiotic with concentrations of 340 µg/mlhave been measured in human crevicular fluid after 14 days (Williams et al., 2001). Researches using
minocycline microsphere as an adjunctive treatment in this network meta-analysis is (Killeen et al., 2016).
1-3-5 Metronidazole gel
Elyzol (Dumex Ltd. Denmark) is a commercial gel that contains 25% metronidazole.
Most anaerobic bacterial species is susceptible toward this antibiotic. It is commonly used as an adjunctive therapy in treatment of severe periodontitis (Van Winkelhoff et al., 2005). Metronidazole gel is reported to maintain level above minimal inhibitory
concentration after 24 hours (Stoltze, 1992). Researches using metronidazole gel as an adjunctive treatment in this network meta-analysis are : (Kinane and Radvar, 1999),
(Radvar et al., 1996), (Riep et al., 1999), (Salvi et al., 2002), (Leiknes et al., 2007), (Rudhart et al., 1998)
1-3-6 Chlorhexidine chip
PerioChip (Perioproducts Ltd. Israel) contains 2.5 mg of chlorhexidine gluconate in a cross-linked, hydrolysed gelatin vehicle(Heasman et al., 2001). Concentrations of the drug remains above the minimum inhibitory concentration for more than 99% of periodontal pocket flora for up to 9 days (Stanley et al., 1989, Soskolne et al., 1998, Schwach-Abdellaoui et al., 2000). Researches using chlorhexidine chip as an adjunctive treatment in this network meta-analysis are : (Salvi et al., 2002), (Heasman et al., 2001), (Kasaj et al., 2007).
1-3-7 Chlorhexidine gel
Chlosite(Ghimas. Italy) is a gel that contains 0.5% chlorhexidine digluconate and 1%
chlorhexidine dihydrochloride. chlorhexidine digluconate is liberated in the first day and achieves a concentration > 100 µg/ml, which is maintained for an average of 6 ~ 9 days(Rusu and Stefan-Ioan, 2005, Gupta et al., 2008). Researches using chlorhexidine gel as an adjunctive treatment in this network meta-analysis is : (Matesanz et al., 2013).
1-3-8 Photodynamic therapy
Photodynamic therapy(PDT) is based on the principle that a photosensitizer binds to the target cells and can be activated by light of a suitable wavelength. Following
activation of the photosensitizer, singlet oxygen and other very reactive agents are produced that are extremely toxic to certain cells and bacteria(Takasaki et al., 2009).
Photosensitizers commonly employed in PDT are toluidine blue O and methylene blue, which have been demonstrated effectively inactivate both gram-positive and
gram-negative periodontal pathogens(Wilson et al., 1993, Sarkar and Wilson, 1993).
The light sources of a specific wavelength mostly applied in PDT range from visible light to the blue of argon lasers (630~980 nm). However, in the case of in vivo and clinical investigations, the diode lasers are the light source predominantly applied (Takasaki et al., 2009). Researches using photodynamic therapy as an adjunctive treatment in this network meta-analysis are: (Muller Campanile et al., 2015, Campos et al., 2013, Carvalho et al., 2015, Chondros et al., 2009, Correa et al., 2016, Lulic et al., 2009, Giannopoulou et al., 2012, Goh et al., 2017)