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Periodontal diseases

Article · June 2017

DOI: 10.1038/nrdp.2017.38

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 PRIMER
Periodontal diseases
Denis F. Kinane1, Panagiota G. Stathopoulou1 and Panos N. Papapanou2
Abstract | Periodontal diseases comprise a wide range of inflammatory conditions that affect the
supporting structures of the teeth (the gingiva, bone and periodontal ligament), which could lead
to tooth loss and contribute to systemic inflammation. Chronic periodontitis predominantly affects
adults, but aggressive periodontitis may occasionally occur in children. Periodontal disease initiation
and propagation is through a dysbiosis of the commensal oral microbiota (dental plaque),
which then interacts with the immune defences of the host, leading to inflammation and disease.
This pathophysiological situation persists through bouts of activity and quiescence, until the affected
tooth is extracted or the microbial biofilm is therapeutically removed and the inflammation subsides.
The severity of the periodontal disease depends on environmental and host risk factors, both
modifiable (for example, smoking) and non-modifiable (for example, genetic susceptibility).
Prevention is achieved with daily self-performed oral hygiene and professional removal of the
microbial biofilm on a quarterly or bi‑annual basis. New treatment modalities that are actively
explored include antimicrobial therapy, host modulation therapy, laser therapy and tissue
engineering for tissue repair and regeneration.

The term ‘periodontal diseases’ encompasses a wide
­v ariety of chronic inflammatory conditions of the
­gingiva (or gums, the soft tissue surrounding the teeth),
bone and ligament (the connective tissue collagen fibres
that anchor a tooth to alveolar bone) supporting the
teeth (BOX 1). Periodontal disease begins with gingi­
vitis, the localized inflammation of the gingiva that is
initiated by bacteria in the dental plaque, which is a
microbial biofilm that forms on the teeth and g­ ingiva
(FIG.  1) . In this Primer, the term gingivitis refers to
plaque-­induced gingivitis. Chronic periodontitis occurs
when untreated gingivitis progresses to the loss of the
gingiva, bone and ligament, which creates the deep
periodontal ‘pockets’ that are a hallmark of the disease
and can eventually lead to tooth loss. Periodontal dis­
ease may contribute to the body’s overall inflammatory
burden, worsening c­ onditions such as diabetes mellitus
and atherosclerosis1–3.
Chronic periodontitis is classified as generalized
1
University of Pennsylvania chronic periodontitis when it affects >10 of the 32 teeth
School of Dental Medicine,
in the human dentition and localized when fewer teeth
240 South 40th Street,
Philadelphia,
are involved4. Although gingivitis and chronic perio­
Pennsylvania 19104, USA. dontitis are initiated and sustained by the microbial
2
Columbia University College biofilm of the dental plaque, genetic and environmental
of Dental Medicine, New York, host factors influence the rate of the disease. Periodontal
New York, USA.
diseases are currently considered to share a simi­
Correspondence to D.F.K.
dean@dental.upenn.edu lar aetio­pathogenesis. In this Primer, we focus on the
mechanisms, diagnosis, prevention and management of
Article number: 17038
doi:10.1038/nrdp.2017.38 gingivitis and chronic periodontitis, which are the most
Published online 22 Jun 2017 common types of periodontal diseases; unless otherwise
stated, the discussion of peri-implant disease (peri-­
implant mucositis and peri-implantitis; BOX 1) does not
differ. Similarly, we highlight any differences between
gingivitis and chronic periodontitis and aggressive and
necrotizing forms of periodontal disease.
Epidemiology
Prevalence
Periodontitis is prevalent in adults but may also occur in
children and adolescents; the amount of tissue destruc­
tion is generally commensurate with dental plaque lev­
els, host defences and related risk factors. A key f­ eature
of both chronic and aggressive periodontitis is site
specificity: the characteristic periodontal pockets and
the accompanying attachment loss and bone loss do
not occur uniformly throughout the dentition (FIG. 2).
Consequently, the definition of a case of periodontitis
heavily depends on which specific thresholds for both
disease extent (the number of affected teeth) and disease
severity (the magnitude of pocket depth, clinical attach­
ment loss and alveolar bone loss at the affected teeth)
are used. Because no sets of thresholds have been con­
sistently used in epidemiological studies, estimates of the
prevalence of periodontitis across populations vary sub­
stantially. A frequently used composite case defin­ition of
periodontitis, based on a combination of clinical attach­
ment loss and probing depth (that is, the measure­ment of
the pocket depth (FIG. 2)), introduced by the US Centers
for Disease Control and Prevention and the American
Academy of Periodontology, has resulted in prevalence

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17038 | 1

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PRIMER

estimates in excess of 50% in the United States5 and
the conclusion that perio­d ontitis is ubiquitous in
elderly individuals. Such findings have raised questions
whether these case definitions are ­suitable for estimating
­prevalence across the entire age range6.
By contrast, epidemiological studies that used
continu­ous measures of probing depth and clinical
attachment loss (that is, the percentage of teeth in the
dentition that present with pockets or clinical attachment
loss that are above specific millimetre thresholds) have
shown that advanced forms of periodontitis that result
in severe loss of supporting structures and substantial
tooth loss affect 10–15% of the population globally 7. This
estimated prevalence range includes both severe aggres­
sive periodontitis (which primarily affects adolescents or
young adults8,9) and severe chronic periodontitis (which
primarily affects adults and whose p ­ revalence increases
with age in all populations10,11).
Risk factors
Several risk factors have been established, some of which
are modifiable (amenable to intervention)12. Cigarette
smoking is a major modifiable risk factor for chronic
periodontitis, as shown in association, progression and
intervention studies13,14, with attributable risk estimates
ranging between 2.5 and 7.0. Smokers have worse perio­
dontal status and experience more-severe tooth loss than
non-smokers, after adjustments for covariates; pro­
spective studies have shown higher progression rates
of chronic periodontitis and tooth loss, and treatment
studies have shown inferior outcomes of both non-sur­
gical and surgical periodontal therapy in smokers com­
pared with non-smokers. Notably, signs of gingival
inflammation can be less pronounced in smokers than in
non-smokers, because of vasoconstriction and enhanced
gingival tissue keratinization12.
Box 1 | Periodontal diseases
• Gingivitis: reversible inflammation confined to the gingiva.
• Peri-implant mucositis: gingivitis that occurs around dental implants.
• Chronic periodontitis: chronic inflammation results in (mostly irreversible) loss of
epithelial tissue, bone and ligament.
• Peri-implantitis: chronic inflammation that occurs around dental implants and results
in bone loss.
• Aggressive periodontitis: can present in localized or generalized forms, both are
early-onset forms of chronic periodontal inflammatory disease, typically manifesting
between puberty and the early third decade of life165. No disease-specific biomarkers
exist that differentiate chronic periodontitis from aggressive periodontitis.
Although current knowledge suggests that both have similar aetiology and
histopathology and might indeed be different ends of the same disease spectrum,
aggressive periodontitis has a more-established heritable component80.
• Necrotizing ulcerative gingivitis and periodontitis: acute forms of periodontal
disease, which are characterized by a rapid course and associated with fusiform
bacilli, spirochetes or viruses — particularly virulent anaerobic microbial biofilm166.
Necrotizing forms are increasingly rare and typically present in debilitated hosts.
• Syndromic chronic periodontitis: a form of chronic periodontal destruction that is
seen as a manifestation of a systemic disease (for example, Chediak–Higashi
syndrome, leukocyte adhesion deficiency and Papillon–Lefèvre syndrome),
commonly associated with major gene defects that affect crucial elements
of periodontal structure or host immune defence.
Diabetes mellitus is the most prevalent and researched
systemic disease that predisposes to periodontitis. The
prevalence and severity of periodontitis are increased in
individuals who have diabetes mellitus of long dur­ation,
and, in particular, in patients with poorly controlled
diabetes mellitus. Conversely, chronic periodontitis can
have a negative effect on metabolic control in individuals
with diabetes mellitus, as it contributes to an increased
inflammatory burden and enhanced insulin resistance15,16.
Notably, the negative effects of diabetes mellitus on the
periodontium manifest at a young age, affecting children
and adolescents with type 1 or type 2 diabetes mellitus16,17.
Epidemiological studies in the United States have
shown that low educational attainment, income below
the federal poverty line, Mexican-American ethnicity
and African-American ethnicity have all been associated
with poor periodontal status in multivariable analyses5,18.
A systematic review has confirmed the global association
between specific socioeconomic and demographic vari­
ables and chronic periodontitis10. Finally, psychosocial
variables have also been associated with various forms of
periodontal disease, but most of the literature on stress
and periodontal conditions is dated, such as the reports of
acute necrotizing ulcerative gingivitis observed in soldiers
on the front line during World War I. Stress is considered
to be immunosuppressive, and acute necrotizing ulcer­
ative gingivitis can occur in immunosuppressed individ­
uals (for example, patients with HIV infection), but there
are insufficient data to precisely determine the role of
psychosocial factors as risk factors for periodontitis19.
Genetic predispositions have been considered to
be important for both the onset and the progression
of perio­dontitis20, with heritability estimates as high
as 50%21. However, the nine genome-wide association
studies that are available so far 22–31 have failed to consist­
ently identify specific single-nucleotide polymorphisms
across populations. In contrast to Mendelian diseases, in
which the pathological phenotype is typically the result
of an abnormality that affects a single gene, genetic pre­
disposition to chronic periodontitis is probably conferred
collectively by hundreds or thousands of genes, whereas
the clinical phenotype is defined by the interplay between
environmental, genetic and epigenetic factors. Epigenetic
factors have gained attention only recently, and additional
research on their role is expected32.
Mechanisms/pathophysiology
The dental plaque
Chronic gingivitis and chronic periodontitis are initi­
ated and sustained by the microorganisms of the dental
plaque33. Indeed, the microbial biofilm has been exten­
sively studied and can comprise around 150 species in a
single person, and up to 800 different species have been
identified in human dental plaque so far 34. The debate
on which species are particularly virulent and can drive
disease onset has lasted decades and is not resolved35,36.
Putative pathogens include Gram-negative anaerobic
bacteria, spirochetes and even viruses, but it is prob­
able that no single pathogen is causative on its own but
rather that dysbiosis (an imbalance of the microbial bio­
film) itself is the pathogenic ‘unit’ (REF. 37). If periodontal

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 PRIMER

a b c

Figure 1 | Healthy and diseased periodontium. a | Healthy periodontal tissues. b | Early Nature
gingivalReviews | Disease
inflammation Primers
(gingivitis;
arrow) can be seen in the gingiva between the central incisor teeth. c | Clinical appearance of chronic periodontitis,
with tissue loss and deep periodontal ‘pockets’ that are a hallmark of disease (arrow).

disease was caused by one or a few specific pathogens, Immunopathogenesis

the preferred therapeutic strategy would be a targeted
alteration of the plaque microbiota rather than total
­biofilm removal36.
Microbial biofilm. Aggressive forms of periodontal dis­
ease have been associated with colonization by specific
clones of Aggregatibacter actinomycetemcomitans in
prospective cohort studies38. Other species, including
Porphyromonas gingivalis, have also been associated with
severe or progressive periodontitis39, but the temporal­
ity (the change over time) of the microbial biofilm and
its association with periodontitis are less clearly estab­
lished. A systematic review 40 concluded that aggressive
and chronic periodontitis could not be discriminated
based on specific periodontal pathogens, a finding that
suggests that the causative microbial biofilm is similar
in both diseases. High-throughput sequencing techno­
logies that characterize the entire periodontal micro­
bial biofilm are expected to substantially expand our
knowledge on the microbial determinants of chronic
­periodontitis on the population level.
Most individuals have experienced multiple viral
infections in their lifetime, and viral DNA or RNA can
still be detected in body tissues long after signs of infec­
tion have dissipated, and these dormant viruses can
reawaken during inflammation flare-ups41. Thus, it is
difficult to establish a cause–effect correlation between
increased viral presence and periodontal disease, and
correlations between periodontal disease and herpes­
viruses might simply be epiphenomena42. Accordingly,
the role of viruses in the aetiopathology of perio­dontal
disease is controversial. However, antiviral therapy
reduced the pocket depth and inflammation in patients
with periodontal disease when used adjunctively with
conventional therapy 43, and is, therefore, recommended
for periodontal treatment by some clinicians44.
Calcification. Dental plaque is present in both uncalci­
fied (soft) and calcified (calculus) forms: supragingival
(on the oral and tooth surfaces) plaque is usually uncalci­
fied, whereas subgingival (in the crevice between the
gingival margin and the neck or root of the tooth) plaque
is typically dark in colour and calcified. Subgingival
calculi are more difficult to remove. Calcification of
sub­gingival plaque is caused by ions from the serum
transudate induced by the inflammation in the perio­
dontal tissues, whereas a supragingival calculus results
from salivary calcium and phosphate ions that aggregate
within the plaque45.
The presence of the microbial biofilm might not be suffi­
cient for the pathogenesis of periodontal disease. Disease
occurs when the balance between the microbial biofilm
and the host is lost, owing to dysbiosis or immune over­
reaction of the host to microbial presence46–48. This
imbalance is complex to unravel, as there are remarkable
variances in both the dental plaque and the host genetic
and immune system profiles37,49, and results in a height­
ened inflammatory state that leads to the tissue damage
observed in periodontal disease50 (FIG. 3).
Epithelial cells function as a physical barrier against
pathogens and elicit innate and acquired immune
responses49. Dendritic Langerhans cells within the epi­
thelium take up microbial antigenic material and bring it
to the lymphoid tissue for presentation to lymphocytes.
Neutrophil, granulocyte and lymphocyte infiltration
into the periodontal lesion ensues: neutrophils attempt
to engulf and kill bacteria, but are overwhelmed by the
magnitude and chronic persistence of the microbial bio­
film. This severe chronic inflammatory response leads
to alveolar bone resorption by osteoclasts, and degrad­
ation of ligament fibres by matrix metalloproteinases
and the formation of granulation tissue51,52. This patho­
physiological situation persists until the tooth is exfoli­
ated or the microbial biofilm and granulation tissue are
successfully removed therapeutically.
Role of T cells. Once lymphocytes reach the site of
­d amage, B  cells transform to antibody-producing
plasma cells. The amount and avidity of the antibodies
are considered important in protection against perio­
dontitis. In addition to the antibody response, T cells
might contribute to cell-mediated immune responses
by stimulating various T helper (TH) cell responses:
TH1, TH2 and TH17, but their relative importance and
the timing of their involvement are still unclear. TH1 cells
might be important during the early stages of chronic
­periodontitis, whereas TH2 cells might be relevant at
later stages53.
However, modern cytokine profiling has revealed
that TH9, TH17, TH22, regulatory T (Treg) cells and other
TH cell subsets as well as various cytokines (such as
IL‑17) are important in periodontal disease immuno­
pathology 54. An imbalance in these T H cell subset
responses could be disease-inducing and might relate
to the function of leukocyte-derived EGF-like repeat
and discoidin I‑like domain-containing protein 3 (also
known as developmentally regulated endothelial cell
locus 1 protein (DEL1), an endogenous inhibitor of

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PRIMER

a Healthy Gingivitis Early-to-moderate Advanced

gingiva periodontitis periodontitis
Alveolar Gingival
bone crevice

Top of pocket
Enamel
Probing
pocket
Cemento-enamel depth
junction Periodontal
therapy
Top of pocket Attachment
Attachment loss
loss Base of pocket
Base of pocket Probing
pocket
depth

Figure 2 | The main stages of periodontal disease. a | Schematics of healthy gingiva, gingivitis, early-to-moderate
periodontitis and advanced periodontitis. b | Measurement of pocket depth. Probing is performed by passing a steel
narrow-diameter probe with distance markings (typically 1 or 2 mm gradations) gently but Nature
firmlyReviews Disease
between| the toothPrimers
and
gingiva, being careful not to further damage the tissue or create artefactual pockets. The probing depth can diminish after
successful treatment as a result of reduced inflammation and gingival swelling, and tightening of the gingival attachment
to the tooth.

neutrophil adherence)55. DEL1 inhibits IL‑17‑induced
oral bone loss in mice, but extrapolating these findings
to the human condition should be done with caution.
Susceptibility
Gingivitis is reversible, but in susceptible individ­
uals progresses to chronic periodontitis 56. Indeed,
susceptibil­ity to gingivitis might reflect susceptibility to
chronic periodontitis57,58, and findings from epidemio­
logical studies indicate that gingivitis precedes the onset
of chronic periodontitis59. Furthermore, the absence of
gingivitis is a good indicator for long-term maintenance
of periodontal health, both on an individual60 and on a
site-specific basis61.
Early studies describing ‘experimental gingivitis in
man’ (REFS 62,63) (a model in which human subjects
stop toothbrushing for typically 21 days and thereby
accumulate plaque and develop gingival inflammation
until brushing is resumed) presented evidence that
suggested that the onset and severity of the inflam­
matory response of the gingiva to the accumulation of
dental plaque differed markedly among participants.
However, the differences were attributed to different
plaque accumulation rates (quantitative plaque dif­
ferences) or differ­ent bac­terial species present in the
microbial biofilm (qualitative plaque differences). Later
studies that used the same model have documented that
individu­als with qualitatively or quantitatively simi­
lar dental plaque could present substantially different
inflammatory responses64,65. Thus, the intensity of the
inflammatory response could represent an individual
trait 66, and susceptibility to periodontal disease might
also depend on host genetic factors67–71.
No specific host factor has been identified as the main
cause of susceptibility to periodontal disease. The obser­
vation that the levels of inflammatory mediators, such
as IL‑1, tumour necrosis factor and prostaglandin E2,
corre­late with the extent of periodontal damage72,73 and
can aggravate the inflammatory response53 suggested that
individuals who produce high levels of these mediators
in response to the dysbiosis will experience more-severe
tissue loss. Reduced numbers or activity of polymorpho­
nuclear leukocytes can also increase the rate and severity
of tissue destruction74. Many drugs, such as phenytoin,
nifedipine and cyclosporine, can stimulate gingival over­
growth and, therefore, modulate pre-existing chronic
periodontitis75. Changes in the levels of circulating
hormones, such as oestrogen, might enhance gingival
inflammation, but do not ­usually increase susceptibil­
ity to chronic periodontitis76. Menopause-associated

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 PRIMER

hormonal changes have been linked to osteoporosis,
but the correlation between this disease or oestrogen
deficiency and a susceptibility to periodontal disease
is unknown. Finally, ­immunosuppressive drug ther­
apy and disease-induced immuno­suppression could
predispose to exaggerated periodontal tissue loss77.
In fact, an impaired immune system generates dys­
functional host responses to infections, resulting in
more-severe disease-induced damage and enhanced
inflammation. Despite the current extensive body of
information on adaptive immunity, both cellular and
humoral, no immuno­globulin markers or lymphocytic
subsets have been definitively linked with increased
­susceptibility to ­periodontal disease78.
Genetics and epigenetics
The role of genetics in chronic periodontitis has been
investigated in family and twin studies. A study in
young Indonesian siblings who did not develop severe
chronic periodontitis despite not receiving regu­
lar dental care suggested that genetic factors could
underlie the less-severe forms of periodontal dis­
ease41,79. Intensive research is underway to identify the
genes and polymorphisms associated with all forms
of periodontal disease. Numerous genes are probably
involved in chronic periodontitis, and the genotypes
of chronic periodontitis might vary across individuals
and ethnicities. Much attention has focused on poly­
morphisms of genes involved in cytokine production69,
but no single-­nucleotide polymorphisms have been
consistently identified45,80.
Family studies could provide information on famil­
ial aggregation, but they cannot distinguish between
genetic and environmental contributions, as environ­
mental factors might also modify gene expression.
Epigenetic changes alter the pattern of gene expression
through methylation or acetylation of DNA bases or
chromatin changes that affect the readability of the
genetic code81, but the epigenetic pathways involved in
the modulation of inflammatory and anti-inflammatory
genes are still poorly understood82. Epigenetics is a rela­
tively new concept in chronic periodontitis research and
could enhance our knowledge on the determinants of
susceptibility and population variance, and supply the
link between genetics, the phenotypes of periodontal
disease and the environment.
Diagnosis, screening and prevention
Diagnosis
The first challenge in treating periodontal disease is a
timely and accurate diagnosis, as the loss of periodontal
bone and soft tissue is incremental and largely irrevers­
ible, and it is particularly difficult as early periodontal
disease is painless and patients rarely seek early care.
Indeed, the early symptom of gingivitis is bleeding while
brushing; pain is rarely reported. The clinical features of
chronic periodontitis include redness, changed texture
and swelling of the marginal gingiva, bleeding of the
gingival pocket area on probing, increased depth of
the perio­dontal pocket (detected by a narrow-diameter
probe (FIG. 2)), destruction of the supporting structures
of the teeth (ligament and alveolar bone), recession of
the marginal gingiva (which exposes the root), increased
tooth mobility and drifting, and, eventually, tooth
loss83. Pain may arise with acute exacerbations owing to
abscesses or dislodgement of teeth caused by weaken­
ing tooth support. However, typical periodontal disease
is painless and it is common for periodontal disease to
have reached advanced degrees of severity before it is
detected and treatment is started.

Innate response
Bacteria Rapid response Polymorphonuclear cells

Keratinocyte NK Neutrophil Keratinocytes

cell
IL-1
IL-8 Dendritic
TNF Macrophage cell
Calculus
Adaptive response IL-1 Antigen presentation
TGFβ
B cell TNF IL-4
CD40 CD8+
IL-10
IL-12 T cell
IL-4 T cell

CD4+ IL-4 TGFβ

Antibodies T cell IL-10 IFNγ

Figure 3 | Immune responses in chronic periodontitis. The host– tumour necrosis factor (TNF), interleukins, interferon-γ
Nature Reviews (IFNγ)
| Disease and
Primers
pathogen interactions that occur at the gingival crevice and periodontal transforming growth factor-β (TGFβ), as well as antibodies raised against
pocket site are characterized by neutrophil and granulocyte the biofilm components. However, neutrophils are eventually overwhelmed
(polymorphonuclear cell) infiltration, which is driven by chemotactic by the magnitude and persistence of the microbial biofilm and are
gradients created by the bacteria and the inflammatory response and ultimately killed or undergo apoptosis or necrosis as they interact with
lymphocyte infiltration that follow dendritic cell antigen presentation. bacteria within the gingival crevice. Scale for the histological inset is
The resulting pro-inflammatory milieu includes cytokines such as ×100 magnification. NK, natural killer.

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PRIMER

Diagnosis of chronic periodontitis is mostly based on
an array of clinical measurements that include clinical
attachment level, bleeding on probing, probing depth
and radiographic findings84 (FIG. 4). Additional infor­
mation, such as medical and family history and specific
clinical features (for example, the location of the lesions
or the quantity of plaque relative to disease progression),
can help to distinguish different types of periodontal dis­
eases85. However, an accurate diagnosis (at specific sites
and of the patient overall) requires recording multi­ple
parameters (including bleeding on probing, probing
depth and clinical attachment level) at six locations
per tooth (whether affected or not), which results in a
laborious diagnostic process that is also dependent on
the expertise of the examiner. Furthermore, this process
needs to be regularly repeated at recall visits to monitor
the disease course86. These clinical parameters are the
best currently available measures for diagnosis; however,
they can only assess the current extent and severity of
the disease. No information can be extrapolated about
future disease activity, owing to the low sensitivity and
low positive predictive value of these tests87.
Once a diagnosis is made, the health care practitioner
should promptly remove aetiological factors (the micro­
bial biofilm on the tooth and gingiva surfaces) and advise
the patient about the possible risk factors (for example,
poor oral hygiene, smoking and uncontrolled diabetes
mellitus) (FIG. 5). Because the modifiable risk factors
are predominantly in the patient’s sphere of control,
successful management of both chronic and aggressive
periodontitis relies heavily on patient motivation and
behavioural changes and is, therefore, challenging.
Disease course
Some individuals might be very susceptible to the effects
of the accumulation of dental plaque and aggressive
forms of periodontitis at a relatively young age (FIG. 6),
whereas others might be resistant and never develop
chronic periodontitis18. In some cases, the disease pro­
gression is slow and the lifetime risk for loss of perio­
dontal function will be minimal, whereas in others it
progresses quickly. In addition, some gingival sites are
more susceptible to developing chronic periodontitis
than others within the same subject 82.
Screening and prevention
The most useful screening for susceptibility to perio­
dontal disease is the detection of gingivitis (self-detection
is based on bleeding from the gingiva upon brushing).
Prevention of gingivitis is a primary preventive meas­
ure for chronic periodontitis and involves retarding
the formation of the microbial biofilm and/or eradicat­
ing it at regular intervals. Prevention is achieved with
self-performed oral hygiene on a daily basis and profes­
sional removal of biofilm on a bi‑annual basis, although
recent data indicate that, for low-risk patients who have
few or no risk factors, professional prophylaxis on an
annual basis may be adequate88. The American Dental

Posterior teeth Anterior teeth Posterior teeth

1
Upper teeth

1 2

2
Lower teeth

Figure 4 | Clinical periodontal chart and intra-oral radiographs of a patient with chronic Nature Reviews | Disease Primers
periodontitis.
Periodontal charts similar to the one depicted are commonly used in dentistry and particularly in periodontology to
document the clinical condition of the patient at the time of initial presentation and after therapy. The charting after
therapy typically shows improvement in the clinical parameters shown in these charts, which include probing depth
(PD; FIG. 2), location of the gingival margin (GM), clinical attachment levels or loss (CAL) and the width of the
mucogingival (MG) junction (measured with a scale in millimetres) on the lingual (inner) and facial (outer) surfaces of
the teeth. The insets show the radiographs corresponding to the identified teeth on the chart. In part 1, the arrows point
to generalized bone loss (10–20%) around tooth 31. In part 2, the arrows point to localized bone loss (80–90%) around
tooth 26. DCM, distal–centre–mesial; MCD, mesial–centre–distal. Images courtesy of A. Aseri, University of Pennsylvania
School of Dental Medicine, Philadelphia, Pennsylvania, USA.

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 PRIMER

Microbial dysbiosis completed. Long-term randomized controlled trials

have shown that, when these basic conditions are met,
non-surgical therapy can be an effective strategy, with
Healthy periodontium no difference observed between non-surgical and sur­
gical therapy when mean values of clinical measures
are compared89. Scaling and root planing are performed
with hand scalers and curettes or ultrasonic instruments,
or both. Hand scalers and curettes are sharp instruments
with one or two cutting edges used for the removal of
calculus, plaque and stain, both supra­gingival and,
in particular, subgingival, which is c­ rucial in perio­
dontal disease; ultrasonic versions of these instru­
Resistance ments vibrate in the ultrasonic range (approximately
Genetic factors
• Innate immune response 25,000–30,000 cycles per second) and can be used,
• Adaptive immune response together with a stream of water, to remove adherent
• Inflammation deposits from teeth. Both manual and ultrasonic instru­
• Other structural components mentation are effective in removing subgingival calcu­
Healthy periodontium Diseased periodontium
lus and altering subgingival microbiota90–92. In addition,
Risk factors both types of instrumentation achieve comparable
Environmental
• Smoking
improvement in clinical parameters (that is, probing
• Dental plaque accumulation depth reduction, clinical attachment level gain and
• Socioeconomic status reduction in bleeding on probing)93,94. Scaling and root
Host-specific planing with power-driven instruments require substan­
• Genetic factors tially less time and cause less soft tissue trauma; however,
• Overall inflammatory burden
these instruments may cause more root damage95.
Figure 5 | Susceptibility to periodontal diseases. Disease progression depends Once initial scaling and root planing have been com­
on the extent and severity of the microbial biofilm challenge (microbial
Nature Reviews dysbiosis) and
| Disease Primers pleted, a 4–6 week period is required for adequate heal­
the host response, which is influenced by protective factors (resistance) and promoting ing of the connective tissue and before reassessment.
factors (risk factors). During the re‑evaluation appointment, diagnostic clin­
ical measure­ments are recorded again and the response
to initial therapy is assessed. If there are no teeth with
Association recommendations for daily home care residual inflammation and pockets, then the patient is
include brushing teeth twice daily for 2 minutes with placed on periodontal maintenance. However, if there is
a soft toothbrush, brushing the tongue, cleaning the residual inflammation and active disease, additional ther­
interdental spaces with interdental aids (such as floss or apy is required, which could be either localized or gen­
interproximal brushes), using a fluoride toothpaste and eralized and either non-surgical or surgical, depending
having a balanced diet with limited between-meal snacks. on the extent and severity of the residual inflammation.

Management Adjunctive therapies

All forms of gingivitis are treated by debridement (the
removal of plaque and calculus) from teeth by scaling
and the removal or reduction of risk factors, followed by
daily home care and professional prophylaxis at follow-­
ups. Chronic periodontitis is treated by debridement
and other mechanical means that can involve surgery
(FIG. 7). Once periodontal clinical attachment and/or
bone loss are evident, the goal of treatment is to control
inflam­mation, arrest disease progression and create the
conditions that will help the patient to maintain healthy,
functional and comfortable dentition in the long term.
Non-surgical therapy
Initial non-surgical therapy for periodontal disease con­
sists of professional removal of both supragingival and
subgingival dental plaque and calculus with scaling
and root planing (deep cleaning with local anaesthesia).
The clinical outcome is largely dependent on the skill of
the operator, the skill and motivation of the patient in
practicing adequate home care and the patient’s compli­
ance with the recommended periodontal maintenance
appointment interval once active treatment has been
To enhance treatment outcomes, several adjuncts to
non-surgical periodontal treatment have been proposed.
These include local delivery of drugs, systemic a­ ntibiotics
and systemic host modulation agents.
Local delivery of drugs. Adjunctive drugs include
antibiotics, such as minocycline and doxycycline,
or antimicro­bials, such as chlorhexidine, that are deliv­
ered directly to the periodontal pocket using a powder,
gel, chip or fibre delivery system for localized treatment.
A systematic review and meta-analysis of studies on
adjunctive local drug delivery concluded that moderate
evidence is available to support the benefits of mino­
cycline gel and microspheres, chlorhexidine chip and
doxycycline gel96. Another review recommended using
adjunctive local antimicrobials in deep pockets or teeth
with recurrent disease97.
Systemic antibiotics. Several regimens that vary in
antibiotic type, dosage, duration and timing of initi­
ation have been proposed; typically, a broad-spectrum
antibiotic is used either alone or in combination with

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17038 | 7

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PRIMER

a b

Figure 6 | Generalized aggressive periodontitis. a | A 27‑year-old woman had a phobia Nature Reviews
about visiting her| Disease Primers
dentist and
failed to brush her teeth adequately. The periodontal condition around the teeth was untreatable, as the attachment was
destroyed by chronic inflammation and bone loss. The patient eventually lost her teeth and was provided with dentures.
b | The radiographic appearance of a case of less-severe generalized aggressive periodontitis.

antibiotic (or antibiotics) targeting Gram-negative bac­
teria, in the usual adult dose range, for 1–3 weeks98.
Three systematic reviews that evaluated different sys­
temic antibiotic regimens in the treatment of chronic
and aggressive periodontitis concluded that the combin­
ation of amoxicillin and metronidazole seems to be the
most potent and resulted in more-pronounced clinical
improvements in probing depth and clinical attachment
level99–101. A systematic review and meta-analysis of stud­
ies on the use of this antibiotic combination in addition
to non-surgical periodontal therapy concluded that there
is moderate-to-strong evidence to support that this treat­
ment strategy results in significantly superior clinical out­
comes in terms of probing depth reduction, clinical
attachment level gain and bleeding on probing reduction
than s­ caling and root planing alone102. These s­ uperior
outcomes were even more pronounced in sites with
­initially deeper pockets of ≥6 mm. The results of the stud­
ies on adjunctive use of systemic antibiotics are promis­
ing; however, additional research is required to define
specific recommendations on several treatment aspects,
such as drug dosage, duration of adjunctive treatment
and appropriate timing during non-surgical treatment to
initiate antibiotic use. In addition, the potential clinical
improvement needs to be carefully evaluated and out­
weigh the potential risks, which include the emergence
of antibiotic resistance, substantial adverse reactions
and drug interactions98. Furthermore, long-term studies
that include tooth loss as an end point in addition to the
­clinical measurements are needed.
Systemic host response modulation. When used in a
sub-antimicrobial dose, doxycycline targets the host
response. Sub-antimicrobial doses do not have anti­
microbial properties and the mechanism of action of the
drug is exclusively through inhibition of matrix metallo­
proteinases103. A multicentre, randomized controlled
trial104 of daily sub-antimicrobial dose doxycycline in
combination with scaling and root planing provided a
defined but limited improvement in periodontal status,
with compliance as a potential issue and long-term
benefits unknown. Host modulation therapy could
be ­beneficial for patients with increased susceptibility 105.
Limitations of non-surgical therapy
Non-surgical periodontal therapy, with or without
adjunctive therapies, is an effective treatment for chronic
periodontitis: it reduces pocket depth and results in the
formation of some new attachment; however, it also
has several limitations, and surgical therapy might be
required to control inflammation and optimize out­
comes. When used for non-surgical scaling and root
planing, periodontal curettes can reach a mean probing
depth of up to approximately 5.5 mm. The mean prob­
ing depth in which a plaque-free and calculus-free sur­
face can be established is <4 mm (REF. 106). However, in
moderate (4–6 mm) and deep (>6 mm) pockets, curettes
have reduced efficacy, and the possibility of achieving
a calculus-free surface substantially increases with
surgical access for scaling and root planing 107. Several
local anatomical factors can contribute to plaque reten­
tion (BOX 2), and surgical access is frequently required
to elimin­ate plaque and calculus at these sites. Surgical
access is also required when recontouring (reshaping)
of osseous defects is necessary to establish a favourable
osseous architecture or when regenerative procedures
are needed to restore lost periodontal structures108.
Surgical therapy
Several surgical approaches are available. Open flap
debridement is a procedure in which a section of the
­gingiva is surgically separated from the underlying
­tissues to provide visibility and access to the lesion.
Pocket reduction surgery includes resection of soft and
hard tissue using various techniques109,110. Regenerative
surgery includes guided tissue regeneration (the use of
barrier membranes to direct the growth of new perio­
dontium, by preventing the epithelium and connective
tissue from growing in areas where bone and perio­
dontal ligament are desired)111, grafting and the use of

8 | ARTICLE NUMBER 17038 | VOLUME 3 www.nature.com/nrdp

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 PRIMER

biologics112. Laser-assisted new attachment procedure
(LANAP)113 has been recently introduced as a con­
servative alternative to surgical therapy. LANAP uses a
Nd:YAG laser for the initial pocket de‑epithelialization
and final fibrin clotting instead of a scalpel and sutures,
and does not include extensive gingival flap elevation.
Treatment outcome
Long-term randomized controlled trials evaluating dif­
ferent modalities of conventional non-surgical and sur­
gical periodontal therapy have shown that all are effective
in improving clinical diagnostic parameters and arrest­
ing disease progression93,114–119. The reported outcomes
have been strikingly consistent among different studies,
independent of location or practice setting (academic or
private). When comparing surgical with non-surgical
therapy, the breakdown rate (disease progression) was
lower for surgical therapy, especially on posterior multi-­
rooted teeth120,121. In fact, surgical access to the diseased
teeth enables a more-accurate determination of progno­
sis; thus, teeth with worse prognosis may be extracted
during the initial surgery, which results in a better long-
term prognosis for the remaining teeth. Appropriate
maintenance and patient compliance with the recom­
mended interval of periodontal maintenance sessions
were key common factors that contributed to long-term
stability of the disease and treatment success93,114–119.
In non-surgical and the majority of surgical perio­
dontal therapies, healing occurs through the formation
of a long junctional epithelium or a new connective
­tissue attachment to the previously diseased root surface.
Regenerative surgical procedures have the potential to
also induce the restoration of lost alveolar bone, perio­
dontal ligament and cementum (the surface layer of the
root), and is the ultimate form of periodontal healing.
A systematic review of guided tissue regeneration con­
cluded that regeneration in intra-bony defects (perio­
dontal defects within the bone surrounded by one, two or
three bony walls) and furcation defects (bone loss at the
base of the root trunk of multi-rooted teeth, where two
or more roots meet) is possible on previously diseased
sites, as evidenced by clinical attachment gain, probing
depth reduction and radiographic bone fill (radiopaque
fill of a previously radiolucent defect in an X‑ray, a find­
ing that on its own, however, does not necessarily mean
that regeneration has taken place); in addition, these
outcomes were significantly better than those obtained
with open flap debridement alone122. Another system­
atic review on periodontal regeneration confirmed these
findings and further added that, for intra-bony defects,
the use of biologics results in clinical improvement that
is generally comparable with that obtained with bone
replacement grafts and guided tissue regeneration, and
that these favourable outcomes can be maintained over
>10 years123,124.
LANAP can induce new attachment and perio­dontal
regeneration113,125 and has the potential to improve clin­
ical outcomes, as shown in a short-term prospective
clinical evaluation126. However, extensive randomized
controlled studies are necessary to evaluate the long-term
efficiency of this procedure compared with the c­ urrent
established non-surgical and surgical approaches.
Periodontal maintenance
Periodontal therapy has the potential to control dis­
ease progression and reduce tooth loss by 10‑fold127–132.
However, the long-term success of periodontal therapy
is strongly dependent on appropriate maintenance after
active treatment has been completed129–133. Periodontal
maintenance consists of the removal of supragingival

Patient with periodontitis

(diagnosed through full-mouth probing and radiographs)

Perform scaling and root planing

Has disease been resolved in all sites?

(Re-evaluation through full-mouth probing)

Yes No

Periodontal maintenance Is unresolved disease localized or generalized?

(full-mouth debridement at regular intervals,
typically every 3 months)

Yes Localized Generalized

No

Is disease controlled in all sites? Scaling and root planing, Systemic antibiotics,
(Evaluation through full-mouth probing local delivery drugs host response modulation
during periodontal maintenance) or periodontal surgery or periodontal surgery

Figure 7 | Decision algorithm for the therapeutic management of chronic periodontitis. Once
Nature diagnosed,
Reviews patients
| Disease Primers
with periodontitis undergo scaling and root planing (deep cleaning), in addition to basic motivation and education on
personal plaque control and reducing modifiable risk factors, such as smoking. If this approach proves successful at
resolving the disease, patients should be offered periodic maintenance therapy comprising debridement (scaling and
root planing). If the disease is not controlled, additional treatment is needed and can comprise antibiotic, host modulation
or surgical therapy.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17038 | 9

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PRIMER

Box 2 | Factors that contribute to plaque retention
• Overhanging restoration: iatrogenic extension of a dental restoration into the
interdental space
• Cervical enamel projection: developmental apical extension of enamel, usually
towards a furcation between the roots of molar teeth
• Enamel pearl: developmental focal mass of enamel that forms apical to the
cemento-enamel junction, typically located in the area between the roots of molars
• Distopalatal groove: developmental anomalous groove usually on the palate close
to the root of maxillary (upper teeth) central and lateral incisors
• Root proximity: the closeness of roots of adjacent teeth, typically associated with
inadequate interdental tissue
and subgingival dental plaque, and is performed at
regu­lar intervals for the life of the dentition. In general,
a 3‑month maintenance interval in patients treated
for chronic periodontitis has been shown93,114–119 to be
adequate and appropriate to ensure long-term success
by disturbing the microbial biofilm before it becomes
pathogenic. The maintenance interval can be further
customized depending on patient susceptibility and the
presence or absence of patient-specific risk factors, such
as smoking, diabetes mellitus or the ability to perform
adequate home care.
Supportive periodontal therapy aims at the long-term
maintenance of the periodontium, dentition, occlu­
sion (the contact between the maxillary (upper) and
mandibular (lower) teeth) and oral aesthetics. This is a
challenging phase of therapy as it relies again on patient
motivation and adherence to strict recall intervals and
requires a reasonable investment in time and energy. In a
population of patients treated in a private practice, com­
pliance with the recommended recall interval was erratic
in approximately 50% of those patients treated for chronic
periodontitis, and complete compliance was achieved in
<20% of these patients134. When measures were taken to
improve compliance (for example, reminder phone calls
and postcards, scheduling the following appointment
at the end of each appointment, reinforcement of the
importance of oral hygiene and maintenance, and edu­
cation of dental practice staff members), this percent­
age increased to >30%; however, approximately 20% of
patients never returned for recall, regardless of the efforts
of the practice135. Lack of compliance can substantially
affect long-term prognosis, as the rate of progression
of treated chronic periodontitis without maintenance
­therapy is similar to the rate of untreated disease133.
Management of peri-implant disease
Essentially, the management of peri-implant mucositis
and peri-implantitis is similar to the treatment of conven­
tional periodontal disease, with two main differences. The
first is that the implant is not surrounded by perio­dontal
ligament and, therefore, the blood supply to the tissue
around the implant is somewhat anatomically l­imited.
The second main difference is that titanium implants are
softer than natural teeth and will scratch with conven­
tional mechanical debridement. Thus, cleaning instru­
ments (scalers and curettes) should be coated with softer
materials, such as polytetrafluoroethylene (also known
as Teflon (Chemours, Wilmington, Delaware, USA)
or ­carbon fibre136, or with titanium as well137. Similar
considerations apply to ultrasonic debridement instru­
ments, and tips made of polyether ether ketone are avail­
able. Recently, even less-abrasive instruments, such as
airflow devices, have been shown to be more effective
in vitro in the removal of biofilm with minimal damage
to the implant surface138.
Quality of life
Periodontal disease is a silent disease, often subclinical,
but can negatively affect eating, aesthetics and speaking
in particular 139. Loss of function due to tooth or implant
loss affects mastication and, therefore, digestion and
can greatly affect nutrition and diet 139–141. This effect
on nutrition has the most detrimental consequences
in elderly individuals: studies have suggested that a
non-functioning dentition can severely impair survival
and correlates with hospital visits and morbidity 142.
The considerable aesthetic consequences of bone and
tooth loss and recession of the gingiva can also affect
quality of life. The aesthetic consequences are most
rele­vant to the patient if the anterior periodontium is
­damaged, as the teeth at the back of the mouth are not
readily seen. Halitosis can be a considerable ­problem
in social interactions143. Disrupted dentition with pre­
dom­in­antly aesthetic consequences has been linked
with poor employment prospects144 and marked social
­shyness and inhibitions.
Comorbidities associated with chronic forms of
perio­dontal disease, particularly chronic perio­dontitis,
can also play a part in patient quality of life. Strong evi­
dence from longitudinal studies links chronic perio­
dontitis with diabetes mellitus in a two-way relationship
— that is, chronic periodontitis worsens diabetes melli­
tus and vice versa. Both diseases are thought to adversely
influence the patient’s metabolic balance and overall
inflammatory burden16. Associations between chronic
periodontitis and cardiovascular disease, stress and obe­
sity have also been supported in the literature, but these
associations might be explained by shared risk f­ actors
and comorbidity, rather than being directly causal (FIG. 5).
Periodontal disease has also been associated with poor
pregnancy outcomes (preterm delivery and low birth
weight), but the body of evidence and interventional
studies21 failed to convincingly prove this correlation.
Periodontal disease and pregnancy outcome might be
linked by shared risk factors, comorbidity, inflamma­
tory burden and metabolic syndrome, but the chances
of a causal correlation are low, as the majority of babies
are born to mothers <30 years of age, whereas chronic
periodontitis generally manifests around 35 years of
age4. This temporal discrepancy could be explained
by hypothesizing that chronic gingivitis is associated
with poor pregnancy outcomes, but the mildness of the
extent and severity of chronic gingivitis and the fact that
chronic gingivitis is common in the global population
would suggest that this correlation is also improbable.
Nevertheless, adequate oral hygiene is undoubtedly
important in reducing or preventing chronic gingivitis
and, therefore, any as yet unconfirmed risk145.

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 PRIMER

Outlook human periodontal disease148. Thus, although immuni­

Diagnostics
Clinical measures, such as pocket depth, clinical attach­
ment level and bleeding on probing, are essential for
the diagnosis of periodontal disease79 and have not
been ­b ettered, despite concerted efforts to discover
bio­markers in saliva and gingival crevicular fluid (the
inflammatory exudate that can be collected at the gingi­
val margin or within the gingival crevice). Greater
awareness of periodontal disease and more-sensitive and
speci­fic diagnostic methods will enable general dentists
to prevent and diagnose chronic periodontitis early and
refer patients for specialist treatment rapidly. The use
of multiple biomarkers for screening, diagnosis and
prediction of disease progression has been extensively
studied; however, only one is currently commercially
available (neutrophil collagenase; also known as matrix
­metalloproteinase 8) in some European countries45.
The ratio between the proteins tumour necrosis fac­
tor ligand superfamily member 11 (also known as recep­
tor activator of nuclear factor-κB ligand (RANKL)),
which promotes osteoclast differentiation and activ­
ation, and tumour necrosis factor receptor superfamily
member 11B (also known as osteoprotegerin), which
acts as a decoy receptor for RANKL, thereby neutral­
izing its osteoclastogenesis-promoting function, shows
promise in detecting bone loss and, therefore, cur­
rent chronic periodontitis activity, but cannot predict
future disease. Many other molecules related to tissue
destruction, such as matrix metalloproteinases45, and
periodontal inflammation, such as cytokines, are being
investigated as possible diagnostic biomarkers, but have
still to meet the sensitivity and specificity requirements
to be used as predictors of disease course146. The natural
history and nature of periodontal disease substantially
complicate the discovery of predictive biomarkers, as
periodontal disease progresses episodically with diffi­
cult to define quiescent and active periods. Clinical
attachment loss remains the strongest predictor of
future attachment loss79, and the absence of certain clin­
ical inflammatory signs, such as bleeding on probing,
is an excellent negative predictor of periodontal inflam­
mation147. Although currently of limited use, in the
future, biomarkers could be developed that would over­
come specificity, sensitivity and utility concerns and be
widely used146.
Vaccination against periodontal disease
Vaccination against putative bacteria that are impli­
cated in periodontal disease has been tested in a mouse
model148. The results suggest that it could be possible
to vaccinate against P. gingivalis infection and that the
immunological protection could manifest through alter­
ation of the TH17–Treg cell balance. Many questions and
potential pitfalls remain, most importantly regarding the
effectiveness of a mouse model of periodontal disease,
as mice are generally not susceptible to the disease and
their immune response is markedly different from that
of humans, and there is lack of evidence on the specific
involvement and importance of TH17‑mediated immuno­
logical pathways in the pathogenesis or aetiology of
zation against periodontal disease could be developed
in the future, it is far from clear what manner it will take
and what elements of immunity could be involved.
Management
Tissue engineering. Regenerating lost tissues is the ulti­
mate therapeutic goal. Novel periodontal therapies have
incorporated gene-based, protein-based and cell-based
tissue regeneration approaches coupled with scaffolding
and guiding biomaterials, which can be resorbable or
non-resorbable and conventional or 3D printed149. The
main focus of these approaches is on regenerating bone
to stabilize teeth or implants, but soft tissue regeneration
is also needed, especially for aesthetic purposes. Guided
tissue regeneration has been associated with highly
variable success, and this technique is now only used
in guided bone regeneration, in which the membrane
barrier is placed under the soft tissue (and is, therefore,
less prone to infection) and used as a scaffold or occa­
sionally as a holding device for bone or bone substitute
grafts150. Membranes have now been designed to deliver
antimicrobial or growth-stimulating agents151.
3D printing of biomaterials and inclusion of plasmids,
peptides, proteins and living cells is a rapidly growing
field152. A 3D‑printed bioresorbable scaffold made of
polycaprolactone with compartments to release platelet-­
derived growth factor has been used in one patient in
Italy to repair periodontal defects, and it is still in place
after >1 year 153. However, the long-term use of these
novel methods needs to be addressed in properly con­
ducted randomized controlled trials before ­becoming
standard of care.
Biological mediators used for bone regeneration
include cells, growth factors and gene therapeutics. Stem
cell therapies are in their infancy and ­numerous safety
and regulatory hurdles remain, but sheets of perio­
dontal ligament cells grown from autologous cells have
been implanted into periodontal lesions151. Common
growth factors being researched are platelet-­derived
growth factor, bone morphogenetic proteins and mol­
ecules implicated in vascular and cell growth154. Gene
therapeutics that use plasmids to insert desired genes
into specific cells in specific periodontal sites are being
assessed155 and are considered safer than viral v­ ectors,
which would have long-lasting and unpredict­able
effects as they would insert the genes into a chromo­
some. Adenoviruses and non-integrating lentiviruses
are being researched, and adenoviral vectors contain­
ing bone morphogenetic protein 7 have been used to
enhance attachment and ­differentiation of osteoblasts
to titanium implants155.
Laser therapy. Lasers have been extensively studied
in periodontal therapy and have not demonstrated
superior­ity to existing mechanical debridement pro­
cedures156. A study compared an Er:YAG laser with
an air-abrasive device: both were similarly effective157.
Air-abrasive devices have also been effectively used
in treating peri-implantitis and demonstrated signifi­
cant improvement over conventional carbon curettes

NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17038 | 11

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PRIMER

in reducing bleeding on probing 158. Lasers have also
been used in antimicrobial photodynamic therapy to
kill microbial biofilm bacteria; however, although the
outcomes seem promising, studies are conflicting, and
the protocols used are so varied to preclude meaningful
comparisons. Thus, using lasers to debride diseased sur­
faces in periodontal disease, either as a replacement for
mechanical therapy or as antimicrobial agents, is not yet
­recommended as an alternative treatment modality 159.
Host response modulation. As the host-specific inflam­
matory response is considered a key aetiopathogenic
­element (FIG. 3), excessive inflammation and failure of the
resolution of inflammation can affect disease outcome.
Research previously focused on understanding the role
of prostanoids and leukotrienes in the propagation of
the inflammatory response in order to manipulate
it, but recently, attention has turned to enhancing the
resolution of inflammation by enhancing the ‘off signal’
and promoting healing 160. Pro-resolving lipid mediators,
which are produced via the arachidonic acid pathways
and include lipoxins and newly discovered resolvins and
protectins161, are key agonists of resolution pathways
that drive restoration of tissue homeostasis, thereby
­enabling the tissue to heal more effectively and enhanc­
ing the tissue resistance to new or ongoing inflamma­
tion. Experiments in animals and humans on the use
of these agonists to actively regulate the inflammatory
response have been promising 162,163. Resolution agonists
do not work by dampening the inflammatory process,
thereby interfering with crucial host defences, but rather
are physiological agents that accelerate the resolution of
inflammation and might improve bacterial clearance164.
The potential for treating perio­dontal disease with these
lipid mediators is apparent, and future clinical studies
are awaited.

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12 | ARTICLE NUMBER 17038 | VOLUME 3 www.nature.com/nrdp

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Acknowledgements
The authors thank M. Benakanakere for assistance in
developing Figure 3.
Author contributions
Introduction (D.F.K.); Epidemiology (P.N.P.); Mechanisms/
pathophysiology (D.F.K.); Diagnosis, screening and prevention
(D.F.K. and P.G.S.); Management (P.G.S.); Quality of life
(D.F.K.); Outlook (D.F.K.); Overview of Primer (D.F.K.).
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
How to cite this article
Kinane, D. F., Stathopoulou, P. G. & Papapanou, P. N.
Periodontal diseases. Nat. Rev. Dis. Primers 3, 17038 (2017).

14 | ARTICLE NUMBER 17038 | VOLUME 3 www.nature.com/nrdp

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