Novel and often bizarre strategies in the treatment of periodontal disease.

Treatment of periodontal disease involves complex mechanical, surgical, and medical modalities. Some of the treatment regimens are patient centered, some involve a great amount of technical expertise and competence from a practitioner, and often involve complex procedures like use of tissue-engineered products. In spite of several advances, treatment of periodontal disease depends on scaling and root planing and various surgical procedures as the mainstay, but results of treatment are not always predictable and are often frustrating. The ultimate aim of periodontal treatment is regeneration of periodontal tissues and more particularly lost alveolar bone support. The treatment options include a myriad of approaches and scientists and researchers have tried various tools and agents to improve alveolar bone status and improve periodontal health. These approaches vary from simple monotherapy with systemic antibiotic usage to exotic and novel procedures like shock wave therapy, photodynamic therapy and application.

INTRODUCTION

Periodontal disease is chronic, nagging, and requires meticulous attention by the clinician, dental hygienist, and great efforts by the patients in the form of compliance. There are considerable variations in clinical presentations of periodontal disease, which have been spoken as disease activity models. Although plaque/biofilm is the principal causative factor, several other host-related, environmentally altered factors seem to be playing at tandem. Control of plaque by mechanical means and use of antimicrobials locally and systemically have been the principal methods of disease prevention and containment. However, mechanical plaque control is tedium and taxing on the patients resources and not many patients have the inclination or mindset to scrupulously adhere to demanding and exacting oral hygiene practices. Use of antimicrobials has its own limitations in the form of return and recolonization of the organisms once there is cessation of antibiotic use and other issues related to their prolonged use.

Although there are several procedures available for regeneration of alveolar bone, the results are not always consistently observed. Alveolar bone stimulation has always been a fertile area of research in periodontal therapy.

A practical, convenient, and pragmatic way to treat periodontal disease has been the dream of every clinician. However, realization of the dream seems to be elusive. The prime concern in any periodontal treatment is a control over the errant microorganisms and resolution of soft tissue inflammation and restoration of lost alveolar support. Resolution of soft tissue inflammation appears to be an established accomplishment after scaling, root planing (SRP) and oral hygiene instructions. Control of pathogenic microorganisms has met with limited success with local and systemic antibiotics and restoration of lost alveolar bone support has met with equivocal success.

Various treatment options are available in the armory of a periodontist including surgical and non-surgical therapy, regeneration techniques, tissue engineering etc. Not satisfied with traditional weapons to combat oral microbiota and restore lost alveolar bone support, ingenious clinicians, scientists, and researchers have turned toward novel and sometimes exotic avenues and explored new frontiers of physical laws, pharmacological molecules, and borrowed ideas and concepts as available for other medical situations. The newer approaches may be listed as follows:

Extracorporeal shock wave therapy

Photodynamic therapy

Electrical stimulation on osteogenesis of alveolar bone

Ultrasonic vibrations

Biofilms and bioelectric effect

Control of subgingival biofilm with fine grain glycine powder polishing

Hyperbaric oxygen therapy

Topical and systemic administration of simvastatins

Local and systemic use of bisphosphonates

Use of Teriparatide

Use of antibiotics as monotherapy

Replacement therapy, use of probiotics

Use of herbs, fruits, flowers, foods to resolve inflammation and improve regeneration

Gene therapy

Use of stem cells

Nanotechnology

Use of newer molecules to resolve inflammation

Therapeutic approaches recently available to control inflammation and bone resorption.

Extracorporeal shock wave therapy

Satish Kumar[1] and workers hypothesized that extracorporeal shock wave therapy (ECSWT) could promote alveolar bone regeneration in experimentally created periodontitis in rats. The methodology involved an episode of 100, 300, or 1000 impulses of shock on both cheeks at energy levels of 0.1 mJ/ mm2. A follow-up up to 12 weeks showed improved alveolar bone levels in ECSWT treated rats compared with those which did not receive the shock wave therapy. The authors concluded that ECSWT could be evaluated as an adjunct in periodontal therapy.

Extra shock waves are high frequency energy waves generated under water with high voltage explosion and vaporization. ESWT has been successfully used in various medical disorders like disintegration of kidney stones, healing of non-healing fractures, tendinitis etc. The exact mechanism of action of ESWT is not understood, but it is believed to stimulate angiogenesis related growth factors, factors and proliferation and proliferation cell molecular antigen. The sum effect is improved vascularization, tissue regeneration, and repair. This paper is the first of its kind, where ESWT is applied in the periodontal field. ESWT has been shown to have bactericidal effect on several microorganisms including A. aureus, S. epidermidis, Pseudomonas aerogenosa, and methicillin resistant streptococcus aureus strains.[2-4]

Photodynamic therapy

Medical applications of photodynamic therapy (PDT) include treatment of cancer, psoriasis, actinic keratosis, rheumatoid arthritis, age related macular degeneration. Broadly, it represents an alternative antibacterial, antifungal, and antiviral approach for drug-resistant organisms including bacteria that grow in the biofilm. Photosensitizers are activated by red light between 630 and 700 nm corresponding to a light penetration depth from 0.5 cm (at 630 nm) to 1.5 cm at (700 nm) which is sufficient for periodontal treatment. Sources of this light include a range of lasers, and at present, diode lasers are used predominantly. Non-laser light sources like light emitting diode (LED) and light cure units have been tried. An ideal photosensitizer should be non-toxic, should display local toxicity only after activation by illumination. Most commonly used phtosensitizers include phenothiazine dyes, methelyene blue, and toluidine blue. PDT resulted in improved clinical parameters and decrease in Tumor necrosis factor-α (TNF) and the ligand for receptor activator of NF-κB (RANKL) levels when used as a monotherapy in aggressive periodontitis compared with SRP.[5] In a randomized, controlled study, patients with chronic periodontitis showed improvement in clinical outcomes when PDT was employed as an adjunct to conventional subgingival debridement.[6]

Electrical stimulation on osteogenesis of alveolar bone

An excellent review of the subject was given by Kuboto[7] and workers in 1995. Electromagentic fields (EMF) have been extensively tried in non-union of fractures, artificial bone defects, regeneration of partial limb etc. Karaki et al.,[8] studied electrical stimulation in periodontal regeneration by applying tissue expanding mesh in artificially created horizontal bone defects in dogs. Callus formation was better in defects treated with mesh compared with contra lateral untreated controls. EMF induced increased osteogenesis was suggested as an attractive method for enhanced alveolar regeneration. Alveolar bone defects treated with guided tissue regeneration (GTR) enhanced EMF showed better results compared with controls.[9] Biphasic direct current has been found to contribute to enhanced osteogenesis, and could be applied clinically to the early bone formation around implants.[10] Electromotive forces used alone or in conjunction with graft material or guided tissue regeneration may lead to a new dimension in periodontal therapy in future.[11] Clinical non-invasiveness of EMF and its widespread applications in orthopedic fields makes it an ideal tool for further research in periodontics.

Use of ultrasonics to control biofilm

Recent research has shown that application of antibiotics/antimicrobials coupled with low power ultrasound, significantly aids in controlling bacteria. Most of the work is done by workers from Brigham Young University, Utah,[12] whose research has demonstrated the bactericidal effect of low frequency ultrasonic waves when combined with antibiotics in both planktonic and biofilm forms. The action of ultrasonics in enhancing antibiotic action is not clear but may be due to perturbation of cell membrane or stress response by the bacteria. Research on ultrasonic applications with antimicrobials on oral biofilms is, however, not yet a fertile field of research although oral biofilm and the consequences there off are of greater significance than many other parts of the body. Probably, the initial equivocal results with ultrasonic applications and paradigm shifts in treatment on tissue engineered outcomes has cooled off the attention and the initial enthusiasm.

Biofilms and the bioelectric effect

Blenkinsopp[13] and workers in 1992 first reported the use of electric fields to enhance the efficacy of antibiotics in killing bacterial biofilms. The research opened up many possibilities, especially when it was also reported that antibiotic concentrations were lower and very low current densities were needed. Most of the subsequent research focused on prevention and treatment of device-related bacterial infections.[16]

Control of subgingival biofilm with fine grain glycine powder polishing

An innovative approach in the control of subgingival biofilm was recently introduced in the form of glycine powder polishing. Several beneficial effects have been attributed to glycine which is an amino acid. The polishing requires a special apparatus and controlled pressure. Supragingivally applied glycine powder air polishing (supra-GPAP) has been shown to remove biofilms in shallow periodontal pockets. A recent randomized controlled trial (RCT) has concluded that sub-GPAP is more efficacious in removing subgingival biofilms in moderate to deep periodontal pockets than SRP.[14]

Use of hyperbaric oxygen therapy

Hyperbaric oxygen therapy (HBOT), also known as hyperbaric medicine, is the medical use of O2 at higher than atmospheric pressure. HBOT is a mode of therapy when patient breathes 100% oxygen intermittently.

Most of the studies are interestingly by Chinese researchers. Chen[1516] studied the effect of hyperbaric oxygen alone, hyperbaric oxygen with SRP, SRP alone, and controls. Clinical parameters, gingival blood flow, and microbiologic assessment were done. Of particular relevance was the effect on anaerobic organisms. HBOT has a detrimental effect on anaerobes. Significant differences were observed in clincial indices, gingival blood flow, subgingival anaerobe number, number of rods, curved rods, fusiform bacteria, and spirochetes by comparison of hyperbaric oxygen+scaling and scaling alone groups. The authors concluded that hyperbaric oxygen had beneficial therapeutic effects on severe periodontitis, which could last more than one year. Alexander et al.,[17] used adjunctive O2 therapy to accelerate clinical improvement in patients with acute nercotizing ulcerative gingivitis (ANUG). O2 therapy seemed to result in rapid clinical improvement with less periodontal destruction.

HBOT is expensive; units are not available for routine use and should be used with caution in view of several general systemic conditions which contraindicate its use. There are some risks associated with indiscriminate use of HBOT. Barotrauma, effect on lungs and ear drums, O2 toxicity, and effect on lens with blurred vision are reported. It should also be used with caution in patients with respiratory infections, high fever, history of thoracic surgery, and emphysema. The possible beneficial effects should be weighed against practical logistics in clinical practice.

Use of statins

Hydroxymethylglutaryl-coenzyme A reductase inhibitors, commonly called as statins, have also been studied with reference to their ability to induce alveolar bone regeneration. Simvastatin was injected into buccal mucosa, and micro computed tomography and histological examination was carried out. Simvastatin increased and maintained a high level of osteoblastic function. It was concluded that topical Simvastatin can stimulate osteoblastic activity and be used topically to reverse the alveolar bone loss in rats.[18]

Recently, using a novel Periodontal inflammatory burden index, it was reported that statin users exhibited fewer periodontal inflammatory injuries and the beneficial effect was attributed to their pleiotropic anti-inflammatory effect.[19] Simvastatin was found to reduce NF-Kappa B and AP-1 promoter activity in KB cells and result in an anti-inflammatory effect on human oral epithelial cells involving Rac1 GTPase inhibition.[20] In a randomized clinical trial, Pradeep and Thorat[21] administered 1.2 mg of simvastatin gel as an adjunct to SRP in patients with chronic periodontitis, and after 6 months, reported promising improvements in gingival inflammation, probing depth, and intrabony defect fill.

Use of bisphosphonates

Bisphosphonates are commonly used for prevention and treatment of osteoporosis, Paget's disease, hypercalcemia associated with malignancy, and osteolysis associated with metastatic bone disease. Mode of action of bisphosphonates is not clear but seems to inhibit osteoclast function, induce their apoptosis, inhibit differentiation of bone marrow precursor cells into osteoclasts. Most of the studies of bisphosphonates are done in animals. In a human study,[2223] 70 mg of alendronate was administered once weekly for two years. No adverse effects were observed, but the study did not show any detectable effect on alveolar bone loss except in patients with low mandibular bone mineral density.

In another clinical study,[24] one tablet of Fosamax (alendronate sodium) was administered every morning for six months in patients with periodontitis. Bone density was significantly more in the alendronate group compared to controls. It had no impact on clinical parameters and the authors suggested that bisphosphonates could play an important role in management of periodontal disease. Lane,[25] in a clinical study, used bisphosphonate for one year and could not find any improvement in bone level. Bisphosphonate with low doses of doxycycline was found to provide beneficial effects in periodontal therapy.[26-28]

Use of teriparatide

Teriparatide is a drug composed of first 34 amino acids of parathromone hormone, and has been known to have anabolic effects on bone and found to be useful in the treatment of osteoporosis and treatment of fractures. Bashutski and workers[29] tested the role of teriparatide in human periodontal defects. Forty patients were treated with periodontal surgery followed by daily injections teriparatide (20 μg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for six weeks. Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity The study subjects need to be complimented for their perseverance to take daily injections for six weeks continuously and such therapy may not be always be practical.

Use of systemic antibiotics as mono-therapy

Lopez et al.,[30] in 2006 reported an unusual and unconventional approach to treat chronic periodontitis in previously untreated patients. The author's surmise was that many periodontal patients do not have access to state-of-the-art periodontal therapy. This is particularly relevant in underdeveloped countries, which are hampered by poor dental health infrastructure. Their study involved administering a course of amoxycillin and metronidazole only to one group and SRP only in another group. Similar beneficial results were observed in both the groups, indicating the effectiveness of antibiotic monotherapy.

Single use of amoxicillin+metronidazole, if the reports are to be believed, would in most instances control periodontal disease and if needed the antibiotics can be replenished periodically. If a life term untreated disease burden was improving with single course of antibiotics, few more courses of such protocol would be a better option than the taxing and exacting non-surgical mechanical periodontal therapy. The topic did raise several eyebrows and an academic storm in the tea cup. Such approach has been labeled as ‘heresy’ and the methodology and conclusions have been questioned.[3132] However, the authors did break convention and dogma and tried to free patients from the shackles of a tortuous and exacting demands of non-surgical mechanical periodontal therapy.

Replacement therapy

Applying beneficial bacteria subgingivally so that they will prevent pathogenic organisms recolonizing after SRP was pioneered by Teughels.[33]

Shimauchi,[34] et al. tested the effect of intake of three tablets daily consisting of freeze dried streptococcus salivarius for eight weeks. Salivary lactoferrin levels and lactobacilli in plaque and saliva were assessed at the end of experimental intervention and compared with those who received only placebo. It was concluded that ‘probiotics could be useful in improvement/maintenance of oral health in subjects at a high risk of periodontal disease.

Foods, flowers, and seeds

Trying an extract of licorice (Glycyrrhiza uralensis), Bodet[35] concluded that licorice extract could be a potent inhibitor of proinflammatory response and could be a potential candidate to prevent and/or treat periodontitis-associated tissue destruction. Eucalyptus extract chewing gum used for 12 weeks had a significant effect on clinical parameters and was claimed to promote periodontal health.[36] Reporting the results of miswak pieces on aggregatibacter actinomycetecomitans and porphyromonas gingivalis, Sofrata[37] concluded that miswak pieces had an antibacterial effect and the effect was due to the presence of volatile active antibacterial compounds.

Testing the association between intake of dietary products and periodontal disease, Shimazaki[38] reported that with daily intake of milk, cheese, lactic acid containing foods (yogurt and lactic acid drinks) may be beneficial for periodontal health. A similar inverse association between intake of dairy products and prevalence of periodontal disease was observed by Al-Zahrani.[39] The role of melatonin has been reviewed by Cutando,[40] who concluded that it may play a role as an antioxidant and immunoregulatory agent and contribute to regeneration of alveolar bone through stimulating type1 collagen production and influence osteoblastic and osteoclastic activity. Anti-inflammatory effect of elder flower (Sambus Nigra) has been studied and it has been suggested as a therapeutic measure to control periodontal inflammation.[41]

Proanthocyanidines from grape fruit seed has potential antioxidant properties and could be considered a potential agent in preventing periodontal disease.[42] The ability of Triphala, an Indian Ayurvedic drug to inhibit the effect of matrix metalloproteinase (MMP)-9 was tested by Abhram and workers,[43] who concluded that it had a strong inhibitory effect on the extracellular matrix degradation during periodontitis. An interesting study assessing the impact of green tea intake and periodontal disease indicated a modest inverse association.[44] Monthly tomato intake seems to have positive relationship in periodontal patients,[45] and systemic administration of lycopene in conjunction with routine scaling has been associated with positive effect on gingivitis.[46] Cranberry juice constituents, Co-enzyme Q, honey, propolis, tea tree oil, dietary fatty acid, and fish oil supplementation have been used in various forms to control gingivitis or moderate periodontal disease.[47-53]

Gene therapy in periodontics

Gene therapeutics – periodontal vaccination: Plasmid DNA encoding Porphyromonas gingivalis fimbrial gene resulted in production of several salivary and serum antibodies in mouse. Immunoglobulin thus secreted could neutralize P. gingivalis and limit its pathogenic ability. Immunization with genetically engineered s.gordoni vector expressing P gingivalis fimbrial antigen acted as a vaccine against P gingivalis induced periodontitis in rats.[54] Recombinant hemagglutinin, which is an important virulence factor of P gingivalis, when injected into rats, gave protection against P gingivalis induced bone loss.[55]

Genetic approach and biofilm antibiotic resistance

It is of common knowledge that biofilm bacteria show great resistance to antibiotics. Gene ndvB, which protects a wild form of Pseudomonas aeuroginosa strain, has been rendered ineffective by isolation of a ndvB mutant strain, which makes it susceptible to antibiotic therapy.[56]

Remodeling following gene transfer by electroporation

Alveolar remodeling can occur with various types of stimuli. Application of electric impulse (electroporation) is one such stimuli mediated through a gene transfer. Using in vivo transfer of Lac Z gene (gene encoding for various remodeling molecules) into periodontium and using plasmid as a vector, Tsuchiya et al.,[57] reported predictable alveolar bone remodeling.

Tight adherence gene to control periodontal disease progression

Tight adherence gene (TAG) is essential for adherence and virulence of Actinobacillus actinomycetemcomitans. Mutant strains lacking TAG and the consequent lack of aggressiveness have been developed.[58] Such mutant strains could minimize colonization of actinobacillus actinomycetemcomitans and control/alter periodontal disease progression.

Antimicrobial gene therapy

Host defense can be enhanced by transfecting host cells with an antimicrobial peptide/protein – encoding gene. Host cells infected with β defensin-2 (HBD-2) gene via retroviral vector showed enhanced antimicrobial activity and improved host defense.[59]

Use of antagonists to TNF α and similar other substances to contain progression of disease

Research on these lines i.e. to suppress inflammatory and harmful substances by gene delivery is being attempted. The process is complicated and still in the animal model stage only. All the gene transfer research is in its infancy and tangible clinical results are yet to unfold.

Stem cells, tissue engineering, and proteomics

Stem cells, tissue engineering, and proteomics have made great inroads into therapeutic approaches of several systemic diseases, and periodontics is no exception to this phenomenon. With the increasing focus on mesenchymal stem cells in the periodontium, stem cell based therapies are not far from being launched. Periodontal ligament stem cells transplanted into immune compromised mice differentiated into cementoblast-like cells, adipocytes and collagen forming cells, and it was suggested that periodontal ligament (PDL) stem cells have the potential to generate cementum/PDL like tissue in vivo.[60]

Nanotechnology and periodontal therapeutics

Nano materials are currently being investigated for novel drug delivery and tissue engineering. Local targeted delivery has been enhanced by use of nanosensors, nanoswitches, and other nano delivery systems. Triclosan nano particles were able to reduce gingival inflammation.[61] Arestin is one such example where tetracycline incorporated into microspheres and has shown promising results when locally delivered into periodontal pockets.

Use of newer molecules to resolve inflammation like resolvins

Resolvins (resolution – phase interaction products) are endogenous mediators that have an anti-inflammatory role. They have been found to be effective in preclinical models of asthma, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, retinal disease etc. They offer an entirely novel biological approach in treatment of several inflammatory diseases.

They reduce neutrophil trafficking, regulate production of cytokines and reactive oxygen species and have been successfully evaluated in ligature induced P gingivalis provoked animal model periodontitis. Prior application of Resolvin E1 prevented animal models from developing periodontitis in contrast to unprotected animals which showed progressive disease. In a recent presentation,[6263] it was reported that ‘local application of RvE1 (Resolvin E1) in small amounts resulted in complete resolution of inflammation and regeneration of bone’. Although still in a testing stage, the role of resolvins seems to be promising and exciting in periodontal armory.

Recent therapeutic approaches available to control inflammation/bone resorption

Recently several medications targeted to suppress inflammation and bone resorption have been evolved and some of these are primarily directed at control of osteoporosis and rheumatoid arthritis. They include TNF-α inhibitors (Adalimumab, Etanaracept, Golimumab, and Infliximab), anti-cytokine agents (Anakinra, Tocilizumab, and AMG714) and inhibitor of RANK/RANKL (Denosumab). The use of some of these agents has been restricted to animal studies where protective effect on experimentally induced periodontitis lesions was observed. Some of them are available for use in treatment of inflammatory diseases like rheumatoid arthritis, but their applications in periodontal disease are yet to take off and the days are not far off.

CONCLUSION

Man is an optimist, and in an attempt to gain an upper hand over periodontal destruction, he has tried various indigenous and sometimes disarmingly simple sources. He has tried heat, light, sound, fruits, flowers, herbs, and as a last resort cells and genes. Good supragingival plaque control in combination with mechanical instrumentation and supportive periodontal therapy can maintain periodontal health for more than 20 years[64] and this can be considered as ‘gold standard ‘of periodontal care.[38] Alternative approaches to this gold standard should be easy to use, affordable, patient friendly, and accessible to large mass of people spread over countries and continents.