The contributions of researchers in the United States to scientific advances in the biological understanding, prevention, diagnosis and treatment of periodontal diseases during the past 150 years have been characterized by scientific partnerships among a dedicated practicing profession, substantial public and private-sector research activity, extensive international collaboration, and strong support from the National Institutes of Health, Bethesda, Md. This overview focuses on the discovery of relationships between dental plaque and the host periodontal tissues, and it highlights only a fraction of the pioneers who shaped new approaches to periodontal disease prevention and treatment. Taken collectively, these efforts have fundamentally changed our understanding of periodontal infections and constitute a revolution in how clinicians treat patients with periodontal disease.
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ETIOLOGY AND PATHOGENESIS OF PERIODONTAL INFECTIONS
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Throughout the 19th century and first half of the 20th century, many theories existed regarding the underlying causes of gingivitis and periodontitis. Among the proposed causes were physiological degeneration of periodontal tissues secondary to aging, circulatory problems, gout, nutritional deficiencies, endocrine disturbances, occlusal trauma, dystrophic anomalies in tooth development, and mechanical irritation arising from local factors such as calcified deposits.1,2 Most of these theories were supported by little or no scientific evidence. After experimental proof of the germ theory of disease was provided in 1876, some investigators, including Willoughby D. Miller, believed that bacteria played an important etiologic role in periodontal diseases.3 However, the concept that bacteria were the principal cause of gingivitis and periodontitis in susceptible people did not become mainstream thought until 75 years later.
Advances in microbiology of periodontal diseases.
The classical experimental gingivitis studies conducted by Harald Löe and colleagues in the mid-1960s resulted in a major shift in how scientists and clinicians viewed the etiology of periodontal diseases.4,5 These studies showed that gingivitis developed in all volunteers who refrained from oral hygiene procedures for a three-week period and that reinstitution of daily dental plaque removal resulted in a return to gingival health. During the development of gingivitis and subsequent return to health, qualitative changes occurred in the composition of the dental plaque microbiota.
In addition, in 1967 Stanley R. Saxe and colleagues6 at the University of Kentucky, Lexington, reported a strong association between dental plaque accumulation and the development of periodontal disease in beagle dogs. These investigators demonstrated that tooth cleaning every other day for 18 months was associated with clinically healthy periodontal tissues; however, quadrants of teeth in the same dogs that were not cleaned developed gingival inflammation and attachment loss.6 In Sweden, Jan Lindhe and colleagues7 confirmed these findings by showing that experimental gingivitis in most beagle dogs progressed to periodontitis across a four-year period if dental plaque was not removed on a daily basis; control animals that underwent daily plaque removal via investigator-applied oral hygiene procedures during the same period did not develop gingivitis or periodontitis.7
Among many critically important studies of the microbiology of periodontal diseases, several are historically significant. In 1964, Paul H. Keyes and Harold V. Jordan8 of the National Institute of Dental Research showed that periodontitis could be transmitted from periodontitis-affected Syrian hamsters to healthy animals by inoculating the healthy animals with Actinomyces viscosus from the diseased animals. One decade later, Michael G. Newman and colleagues9 reported that patients with "periodontosis" (that is, localized aggressive periodontitis) harbored a disease-specific subgingival microbiota; this finding challenged the prevailing assumption that periodontosis was a degenerative disease and suggested strongly that the disease was an infection.
According to Fine,10 the results of studies conducted by Theodor Rosebury and his students Solon A. Ellison and John B. MacDonald of the pathogenic potential and virulence of the aerobic and anaerobic components of the indigenous oral microbiota supported the concept that gingivitis and periodontitis are infections. The advent of improved laboratory methods for culturing anaerobic bacteria revealed that some bacteria in plaque are more important than others as causative agents of periodontal infections. Moreover, these studies concluded that periodontal infections are not caused simply by an increased quantity of dental plaque on the teeth; rather, the composition of the microbial community is of considerable etiologic importance.10 A historical review11 of evidence supporting the bacterial etiology of periodontal diseases includes many scientists who contributed to these major advances in periodontal microbiology, notably Ronald J. Gibbons, Sigmund S. Socransky, Anne D. Haffajee and Anne C.R. Tanner at the Forsyth Institute, Boston, and Lillian V. (Holdeman) Moore and William E.C. Moore12 at the Virginia Polytechnic Institute, Blacksburg, Va.
Walter J. Loesche13 summarized this concept in a discussion of nonspecific versus specific hypotheses regarding the microbial etiology of periodontal infections. Some authorities, including Rosebury, favored the nonspecific plaque hypothesis in which increased numbers of indigenous bacteria (that is, an increased plaque biomass) overwhelm host defenses and result in periodontal disease. Other investigators, such as MacDonald, favored the specific plaque hypothesis in which a small number of specific bacteria are responsible for triggering the tissue damage observed in inflammatory periodontal diseases.10
In the 1990s, Socransky and colleagues14 used cultivation methods and DNA probe technology to show statistically significant associations between clusters of indigenous bacteria in the subgingival microbiota and the presence and progression of periodontitis. It became clear that bacteria such as Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Campylobacter rectus, Micromonas micros, Streptococcus intermedius, Eubacterium nodatum, Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans and Prevotella intermedia are important members of the consortium of microorganisms that cause periodontitis.
The major microbiological conclusions established during this period include the following:
- – periodontal infections are polymicrobial;
- – the causative agents are part of the indigenous (normal) microbiota;
- – the amount of dental plaque is of etiologic importance;
- – some bacteria in dental plaque are more pathogenic than others.
Of equal scientific importance was the demonstration by several groups, including those led by John W. Costerton and colleagues15 and Paul E. Kolenbrander and colleagues,16 that dental plaques are highly organized bacterial biofilms. From a therapeutic perspective, these biofilms are complex polymicrobial communities that are resistant to externally applied antimicrobial agents and antibacterial host mechanisms.17
It is now known that only about 50 percent of the oral microbiota can be grown in the laboratory by using modern cultivation techniques.18 It is highly likely that the other, yet-to-be-cultivated 50 percent contains micro-organisms that are of etiologic importance or play important roles in biofilm ecology. Many investigators are applying gene-detection methods to determine the presence of uncultivable components of dental biofilms.19–22 What has emerged from this work is the extraordinary diversity of oral microbiota in health and disease. It is likely that this work will lead to a better understanding of how oral biofilms form, mature and interact with the host to cause disease. Novel treatment approaches and intervention strategies will result from discoveries dealing with the mechanisms of biofilm-host interactions.
Advances in pathogenesis of periodontal diseases.
The early history of periodontal pathogenesis was dominated by the premise that all people are equally susceptible to developing periodontitis and that untreated gingivitis progresses to periodontitis linearly over time. On the basis of general medical pathology models, researchers believed that most of the destruction of periodontal tissues during the course of the disease was due to inflammatory or degenerative/atrophic processes.23 Until the late 1960s, researchers based their studies primarily on observations and individual interpretations of the histologic changes in the diseased tissues. A consistent observation was that the affected tissues were chronically inflamed at both the clinical and histologic levels. Unfortunately, the results of morphological studies alone were unable to explain the mechanisms responsible for the tissue destruction at inflamed sites.
When the results of microbiological studies showed clearly that gingivitis and periodontitis are infections, investigators began to unravel the complex mechanisms of how bacteria could trigger destructive inflammatory responses by the host. In addition, innovative ultrastructural studies conducted by Max A. Listgarten24 clarified the relationship of junctional epithelium to the tooth. He also made major contributions to understanding interactions between microbiota and periodontal tissues in health and disease.25
In 1976, Roy C. Page and Hubert E. Schroeder26 documented a dynamic series of inflammatory events in the development of periodontal lesions. After decades of work by many researchers, it became clear that the progression of periodontitis was neither linear nor an automatic consequence of gingivitis; rather, it could assume a number of clinical presentations depending on the nature and radius of effect of the infecting bacteria, periodontal anatomy, genetic predisposition and expression of the host inflammatory response. Critical variables also included the size, location and composition of the biofilm; the frequency and duration of epithelial ulceration; the everyday habits of the host; and the regularity of oral care.
Indeed, most of the tissue damage found in patients with periodontitis appeared to result from host responses to bacterial challenges rather than from direct lytic effects of the pathogenic micro-biota. Moreover, results of practice-based studies challenged the prevailing concept that all patients are equally susceptible to periodontal infections, because some did not respond well to conventional treatment.27,28 The results of longitudinal epidemiologic studies confirmed these observations, demonstrating that only a subset of the population developed severe periodontitis.29,30
In the late 1990s, emerging evidence suggested that the intensity of inflammation and susceptibility to periodontal damage after a microbial challenge were mediated by the host response, including genetic polymorphisms.31 Observational studies of twins have shown that a significant portion of the population variance in periodontal disease prevalence can be attributed to genetic factors.32,33 Also, it appears likely that genetic changes caused by environmental insults affect the clinical phenotype observed in patients with periodontal infections.34
A number of risk factors associated with periodontitis, such as persistent exposure to microbial challenges, chronic inflammation, smoking and diabetes, are known to produce strong epigenetic changes in affected tissues.34 The results of epidemiologic studies indicate that smoking is an especially important risk factor.35,36 Furthermore, osteoclast-mediated bone loss, a hallmark of periodontitis, appears to be triggered by a cascade of host-response events involving the receptor activator of nuclear factor kappa B [RANK]), the RANK ligand (RANKL) and osteoprotegerin (OPG). Chronic periodontal inflammation may induce increases in the RANKL-OPG ratio, which stimulates osteoclast maturation from precursor cells.37
An increased understanding of the inflammatory response and the natural mechanisms of its resolution suggests that control of inflammation is at least as important as is antimicrobial therapy in the treatment of periodontal infections.38 Future models of the pathogenesis of inflammatory periodontal disease will incorporate genomic, proteomic and metabolomic data into dynamic biological networks that include mechanisms of disease initiation and resolution.39
Potential effect of periodontitis on general health.
During the past two decades, investigators have reexamined the possibility that untreated periodontal infections can have an adverse effect on general health and that other diseases can contribute to periodontal pathogenesis. The results of these studies40–42 suggest that untreated periodontitis may be a risk factor for myocardial infarction, nonhemorrhagic strokes and adverse birth outcomes. In addition, evidence indicates that periodontal infections may interfere with the metabolic control of diabetes mellitus.40 The presence of such associations may reflect risk factors common to periodontitis and other chronic inflammatory diseases. Although this is a highly important area of ongoing investigation, the results of observational and interventional studies vary and the relationship between periodontal disease and general health remains unclear.
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PREVENTION AND TREATMENT OF PERIODONTAL DISEASES
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Dental calculus.
Long before investigators recognized that gingivitis and periodontitis are infections caused by indigenous oral microbiota, many clinicians observed that the frequent removal of acquired deposits from teeth resulted in a noticeable improvement in overall periodontal health. This observation led influential clinicians such as John W. Riggs43 and G.V. Black44 to conclude in the 1880s that dental calculus was a major local irritant that caused periodontal inflammation. However, no universal consensus existed with regard to this issue.1,2 As a result of the confusion regarding the etiology of periodontitis, treatment included a range of therapies including dietary changes, gingival massage, local application of caustic chemicals, occlusal adjustment, ingestion of patent remedies, removal of local irritants and surgical resection of affected tissues. In some situations, dentists and patients considered periodontal disease to be untreatable, with tooth extraction being the ultimate management strategy.
At the beginning of the 20th century, there were two major approaches to treatment of periodontitis. One approach, advocated by many influential practitioners in the United States and Europe, involved the use of surgical resection of periodontal pockets followed by curettage of the underlying bone.44,45 These practitioners thought that the bone was necrotic or affected by a carious process that caused chronic osteitis.44,45 Advocates of this approach considered the soft tissues of the pocket wall to be irreversibly damaged by pus at the site, as well as by mechanical irritation from dental calculus.
Proponents of the second approach held that the disease was caused by local irritation from dental calculus, and the underlying bone was not affected. Practitioners in this group included Riggs43 and William J. Younger46; they opposed the gingival resection approach in favor of the nonsurgical removal of acquired deposits followed by a rigorous program of oral hygiene.
By the middle of the 20th century, the results of many multidisciplinary studies confirmed that the alveolar bone of patients with periodontitis was neither necrotic nor carious.23 In addition, the concept that periodontal diseases are plaque-induced infections was becoming widely accepted by the profession.23 Many clinicians still advocated surgical pocket reduction to create a gingival architecture that would facilitate oral hygiene and periodontal maintenance procedures.
Surgical intervention.
Advocates of surgical intervention included Henry M. Goldman,47 Irving Glickman48 and Saul Schluger.49 Goldman claimed that gingivoplasty would create "physiologic" gingival contours that were "self-cleansing."47 Glickman stated that scaling and root planing was not required before surgery and described a method for eliminating periodontal pockets that consisted of the initial resection of the diseased periodontal pocket wall and subsequent removal of calculus and smoothing of the tooth surface.48 Schluger promoted the use of osseous resection during periodontal surgery on the basis of the hypothesis that healing patterns of the periodontal soft tissues are determined by the hard tissues with which they are in contact.49
Nonsurgical intervention.
Advocates of the nonsurgical approach to treatment of periodontitis included Russell W. Bunting,50 Isador Hirschfeld,51 Arthur H. Merritt52 and Dickson G. Bell.53 These clinicians promoted the concept that most patients with periodontitis could be treated satisfactorily without surgical intervention. They believed that surgical intervention was a treatment of last resort and should be used only in the most advanced cases in which subgingival access for scaling and root planing was impossible without surgical entry.
Scientific data supporting either approach to periodontal therapy did not exist until publication of a series of studies by a team of investigators from the School of Dentistry, University of Michigan, Ann Arbor. These critical investigations of the efficacy of periodontal treatment are now known as The Michigan Longitudinal Studies.54–58 The team was led by Sigurd P. Ramfjord, a Norwegian dentist who came to the University of Michigan in 1946 to study under Bunting, who was then dean of the School of Dentistry. Ramfjord (see photograph59) earned a master’s degree in periodontics and a Doctor of Philosophy degree in pathology and then joined the faculty.60 Taken collectively, these clinical investigations provided the first data showing that nonsurgical and surgical forms of periodontal therapy were effective in resolving periodontal infection and inflammation, and they resulted in sustained repair of periodontal tissues when combined with an appropriate posttreatment maintenance program.
Investigators throughout the world have replicated these results in many studies.61,62 It now seems clear that the choice of nonsurgical or surgical treatment depends on anticipated patient-centered outcomes (such as discomfort, root sensitivity, esthetics), as well as on traditional clinical outcomes, such as a reduction in probing depths and gains in clinical attachment.62 The Michigan Longitudinal Studies were randomized clinical trials (RCTs) that were the first of their kind in periodontology. Two of Ramfjord’s legacies were the introduction of RCTs to periodontology and the promotion of an evidence-based approach to clinical practice.
Adjunctive use of antimicrobials.
An important advance in the past 100 years has been clarification of the benefits and limitations of antimicrobial agents as an adjunct to mechanical periodontal therapy. W.D. Miller3 was among the first to suggest that antiseptics applied topically or via mouthrinsing might be useful in the treatment of periodontal diseases. The results of well-conducted clinical trials demonstrated that topically applied antiseptics, particularly chlorhexidine, were highly effective in the treatment and prevention of gingivitis.63 However, use of topical antimicrobials in the treatment of periodontitis, in which infecting bacteria are sequestered in biofilms within deep periodontal pockets, has been less effective. The results of many clinical trials indicated that irrigating or rinsing with antimicrobial agents as stand-alone treatments for periodontitis was insufficient to eliminate or control periodontal infections because of the inherent antimicrobial resistance of biofilms, as well as difficulties in delivering the drugs to subgingival sites.64
Pitcher and colleagues65 reported that vigorous swishing with mouthrinses did not impel the antiseptics into subgingival infected sites. They concluded that the role of topically applied antiseptics is strictly adjunctive to mechanical disruption and removal of biofilms. Under such conditions, the limited adjunctive effects of antimicrobial agents in treating these infections are enhanced somewhat by placing slow-releasing vehicle preparations directly into the periodontal pocket.66
Systemically administered antibiotics gain access to infected periodontal sites via the circulatory system. In a meta-analysis of data from a large number of clinical trials, Haffajee and colleagues67 found that systemic antibiotic therapy, combined with mechanical removal of plaque via scaling and root planing, had beneficial adjunctive effects, including gains in clinical attachment levels and reductions in probing depths. The clinician’s decision to administer antibiotics is complicated by the possible development of microbial resistance to the drug, allergic reactions, gastrointestinal disturbances and other side effects.
Future basic research regarding the mechanisms of the initiation and maturation of dental plaque likely will lead to novel therapeutic ways to interfere with and disrupt these disease-producing biofilms.
Repair and regeneration.
Throughout the first half of the 20th century, many authorities, including Black, believed that once periodontal tissues were detached from the teeth as a result of periodontitis, "there is no chance whatever for a reattachment."68 Although this view was not held universally, it was the prevailing opinion until clinicians began publishing practice-based series of cases in which therapy resulted in the clinical closure of periodontal pockets with radiographic evidence of osseous repair. Among these publications was a report by John F. Prichard69 in which treatment resulted in dramatic osseous repair, especially of narrow three-walled defects.
As the field of periodontics matured from 1970 to 2000, investigators in many controlled studies evaluated the effects of periodontal flap procedures alone compared with flap procedures combined with the insertion of various bone-replacement graft materials. In a systematic review and meta-analysis of these studies, Reynolds and colleagues70 concluded that bone-replacement grafts resulted in statistically significantly increased bone and clinical attachment levels and reduced probing depths compared with flap procedures alone.
Guided tissue regeneration.
The next major advance in periodontal regeneration was the proof-of-principle introduction of guided tissue regeneration (GTR) procedures in 1982. Sture Nyman and colleagues71 placed a barrier membrane between the periodontal flap and a tooth scheduled for extraction in a patient with severe periodontitis. This procedure temporarily excluded the gingival epithelium and connective tissue from the osseous defect and allowed pluripotent cells from the periodontal ligament to colonize the wound. The results of histologic studies showed partial regeneration of lost periodontal tissues, including the formation of new cementum, bone and a functional periodontal ligament.71 Subsequent investigations reviewed in a meta-analysis72 of the clinical effectiveness of GTR procedures suggest that these procedures can promote gains in clinical attachment levels and reductions in probing depths.
Also during the past two decades, researchers have shown an increasing interest in studying the role of growth factors in tissue repair and regeneration.73,74 Growth factors are naturally occurring mediators produced by a variety of cells that affect the complex cascade of events during wound healing. Growth factors act in a coordinated fashion that regulates the timing of cell division and recruitment of progenitor cells, cell differentiation and synthesis of the extracellular matrix.
Scientific progress in this area has led to the isolation of natural growth factors and the development of recombinant forms that have been evaluated preliminarily for their effect on periodontal regeneration in humans.73 Advances in developmental and molecular biology, human genetics, proteomics, nanotechnology and stem cell biology have set the stage for discoveries that likely will soon allow clinicians to manipulate sophisticated tissue-engineering procedures required for the predictable regeneration of periodontal structures.74
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MAJOR INFLUENCES AND FUTURE ADVANCEMENTS
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Major influences on periodontology in the United States in the past 150 years include strong interrelationships among the American Dental Association, schools of dentistry, clinician-scientist research centers, private sector industry and insurance carriers, and the practicing dental profession.
The American Academy of Periodontology, Chicago, also has played a major role in supporting patient care, encouraging research in periodontal disease biology and treatment, and promoting international scientific collaboration. The academy was founded in 1914 by Drs. Gillette Hayden and Grace Rogers Spalding. Spalding served as the editor of the Journal of Periodontology, first published in 1930. Subsequent editors were Maynard K. Hine, Henry M. Goldman, Timothy J. O’Leary, William C. Hurt, Robert J. Genco and Kenneth S. Kornman, all of whom made major contributions to dental research and established the journal’s reputation for scientific excellence (Alice DeForest, executive director, American Academy of Periodontology, written communication, June 2009).
The American Association for Dental Research and the International Association for Dental Research, Alexandria, Va., have been critically important in the discussion and dissemination of research findings applicable to treating periodontal diseases (Christopher H. Fox, executive director, American and International Associations for Dental Research, written communication, June 2009). The National Institute of Dental and Craniofacial Research, Bethesda, Md., has been essential in its support of research that has advanced the understanding of periodontal disease biology and treatment.
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CONCLUSIONS
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In the future, periodontal therapy in the United States will build on the remarkable scientific advances made during the past 150 years. Although the mechanical removal of biofilms and its products, combined with professional periodontal maintenance, will remain a cornerstone of care, new approaches to the prevention, diagnosis and treatment of periodontitis are well within sight.
On the horizon are major breakthroughs in understanding essential mechanisms that mediate and resolve tissue destruction in periodontal inflammation. Such discoveries will provide new tools for regeneration of periodontal structures and clarify associations between periodontitis and other chronic inflammatory diseases. The results of fundamental microbiological research will lead to innovative methods of identifying and altering pathogenic biofilms. The rapid evolution of implant therapy as an integral part of periodontal treatment will continue, with major advances occurring in establishing a ligamentous attachment to alveolar bone. As a result of these scientific advances, new generations in the United States can expect to retain a healthy and functional dentition for a lifetime.
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ABSTRACT
ETIOLOGY AND PATHOGENESIS OF...
